Natural Nitrogenous Sesquiterpenoids and Their Bioactivity: a Review

molecules

Review Natural Nitrogenous Sesquiterpenoids and Their Bioactivity: A Review

De-Li Chen 1,2 , Bo-Wen Wang 3, Zhao-Cui Sun 1, Jun-Shan Yang 1, Xu-Dong Xu 1,* and Guo-Xu Ma 1,2,* 1 Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 151, Malianwa North Road, Haidian District, Beijing 100193, China; [email protected] (D.-L.C.); ﬂ[email protected] (Z.-C.S.); [email protected] (J.-S.Y.) 2 Hainan Branch of Institute of Medicinal Plant Development, Chinese Academy of Medicinal Sciences & Peking Union Medical College (Hainan Provincial Key Laboratory of Resources Conservation and Development of Southern Medicine), Haikou 570311, China 3 School of Chemical Engineering and Technology, Hainan University, Haikou 570228, China; [email protected] * Correspondence: [email protected] (X.-D.X.); [email protected] (G.-X.M.); Tel.: +86-010-57833296 (X.-D.X.) Academic Editor: Anna Carbone Received: 6 May 2020; Accepted: 22 May 2020; Published: 27 May 2020 Abstract: Nitrogenous sesquiterpenoids from natural sources are rare, so unsurprisingly neither the potentially valuable bioactivity nor the broad structural diversity of nitrogenous sesquiterpenoids has been reviewed before. This report covers the progressd uring the decade from 2010 to February 2020 on the isolation, identiﬁcation, and bioactivity of 391 nitrogen-containing natural sesquiterpenes from terrestrial plant, marine organisms, and microorganisms. This complete and in-depth review should be helpful for discovering and developing new drugs of medicinal value related to natural nitrogenous sesquiterpenoids.

Keywords: nitrogenous sesquiterpenoids; celastraceae; marine sponge; fungi; bioactivities

1. Introduction The natural products commonly termed ‘secondary metabolites’ in contrast to ‘primary metabolites’, are produced byorganisms in order to provide an evolutionary beneﬁt [1]. Natural products as a major chemical resource, have played a signiﬁcant role over the last 200 years in treating and preventing diseases, and continue to serve as important agents in modern drug discovery due to their characteristic chemical spatial orientation, which enables them tointeract with their natural and other biological targets [1–4]. Recently, half of new drugs reported were naturally occurring or constructed on the basis of some natural chemical framework [4–6]. Sesquiterpenoids are the largest class of natural terpenoids, with a structural diversity that includes thousands of compounds and more than 100 skeletal types [7]. Many of them show ‘drug-like’ chemical properties, including alkylating center reactivity, lipophilicity, and favorable molecular geometry and electronic features, and have attracted considerable interest due to their pronounced biological activities [8,9]. Meanwhile, sesquiterpenoids that contain nitrogen bonds constitute a fascinating group with enormous structural diversity [10]. Interestingly, it is notable that nitrogenous sesquiterpenoids are rare innatural sources, and there are only a few hundred such compounds that contain the element N known to be produced bycertain species. Functionally and biologically important to humans, have caught the attention of a number of scientists, and extensive phytochemical and biological investigations of nitrogenous sesquiterpenoids from natural sources have been carried out by researchers at the recent ten years [10–12].

Molecules 2020, 25, 2485; doi:10.3390/molecules25112485 www.mdpi.com/journal/molecules Molecules 2020, 25, 2485 2 of 32

While the scientiﬁc community is generally aware of the rarity of the N bond in natural sequiterpenoids, and there are many reviews providing extensive coverage on sesquiterpenoids [11,12], including the naturally occurring disesquiterpenoids [1,13,14], natural products containing a nitrogen-nitrogen bond [15] or nitrogen-sulfur bond [16], neither the potentially valuable bioactivity nor the broad structural diversity of nitrogenous sesquiterpenoids has been systematically reviewed during the past ten years. In this review, nitrogenous sesquiterpenoids from biological sources, including plants, microorganisms, and marine resources, will be considered. In order to be as comprehensive and clear as possible, the natural nitrogenous sesquiterpenoids have been segregated by structural class and compounds covered in the past decade included where appropriate. This report provides a systematic review of the isolation, structural characterization and biological activities of these compounds since 2010, if known.

2. Species Containing Nitrogenous Sesquite Rpenoids and Their Bioactivities

2.1. Dihydroagar of Uran Sesquiterpenoids Nitrogen-containing dihydroagarofuran sesquiterpenoids feature several ester groups on a highly oxygenated tricyclic scaffold, and their polyesterified macrolide sesquiterpenoid pyridine alkaloids possess a characteristic macrocyclic dilactone skeleton consisting of a dicarboxy licacid moiety, 2-(carboxyalkyl)nicotinic acid, and a polyoxygenated dihydro-β-agarofuran sesquiterpenoid (Figure1 and Table1). The hydroxyl groups of the latter are usually esterified by various organicacids including acetic, benzoic, furanoic, nicotinic, and cinnamicacids. The 2-(carboxyalkyl)nicotinic acid moiety originates from evoninic acid, wilfordic acid, hydroxywilfordic acid, ortheir congeners. The number, position, and configuration of these substituents create a largenovel chemical diversity and exhibit abroad range of biological activities. Dihydroagarofuran sesquiterpenoids were considered the most widespread and characteristic metabolites of the plants of the Celastraceae. Compounds 1–12 were isolated from the roots of Maytenus mekongensis [17]. Compounds 1–5 having wilfordic acid moieties, either with or without a 9 -OAc group, exhibited comparable antiplasmodial activities, with IC values of 3.1 10 3, 0 50 × − 3.9 10 3, 3.5 10 3, 3.1 10 3 and 2.5 10 3 mM respectively, while compounds 10–12 with evoninic × − × − × − × − acid moieties showed no inhibitory activity. Compounds 12–29 were extracted from the dried roots of Tripterygium wilfordii [18]. Compound 22 displayed 22.3% inhibitory activity against HSV2 in vitro at 0.5 mg/mL, and acyclovir 66.3% inhibitory activity at 0.5 mg/mL. Compound 28 showed 31.7% inhibitory activity at 0.25 mg/mL, while acyclovir displayed 60.6% inhibitory activity at 0.25 mg/mL. Compounds 30 and 31 were obtained from the fruits of Celastrus orbiculatus Thunb [19]. Hypoglaunines E (32) and F (33) have been purified from the root barks of Tripterygium hypoglaucum and showed no cytotoxic activities against five cancer celllines [20]. Triptersinines A–H, L (compounds 34–42), peritassine A (26), wilfordinine A (43), hypoglaunine A (44), hypoglaunine E (32), wilfordinine E (45), euonine (46), wilfortrine (21), euonymine (12) were extracted from the leaves of Tripterygium wilfordii, and compounds 26, 34, 43, and 46 showed moderate inhibitory effects onnitric oxide production in LPS-induced macrophages at 5 µM[21]. Compounds 47–49 were identified from thestems of Euonymus alatus [22]. Triptersinines M–T (compounds 50–57) and wilforgine (18) have been extracted from the the leaves of Tripterygium wilfordii, and compounds 50, 51, 54, 57, and 18 showed moderate inhibitory abilities on NO production and no influence on cell viability by the MTT method, the other compounds exhibited weak effects [23]. Compounds 7, 25, 58–91 were obtained from the dried roots of Tripterygium wilfordii [24]. Tripterygiumine Q (81) exhibited immunosuppressive activity with an IC50 value of 8.67 µM, and no cytotoxicity was observed even at a dose of 100 µM. Triptonine B (82) not only exhibited immunosuppressive activity with an IC50 value of 4.95 µM, but also showed cytotoxicity with an IC50 value of 26.41 µM. Compounds 92–95 were isolated from the leaves of Maytenus spinosa [25], and the isolates displayed no anti-HIV activity. Tripterygiumines S-W (96–100), Molecules 2020, 25, 2485 3 of 32 wilfornine A (101), wilfornine D (102), tripfordine A (103), 2-debenzoyl-2-nicotinoylwilforine (104) along with 12–13, 18–20, 25, 75, and 87 were purified from the roots of the Tripterygium wilfordii, and found that 13 and 96 possessed potent nitric oxide inhibitory activity with IC50 values ranging from 2.99 to 28.80 µM, without any effect on the cell viability of RAW 264.7 cells [26]. Accordingly, compounds 13 and 96, especially 13, were identified as promising candidates for further scientific investigation of their potential use as anti-inflammatory agents. Compound 105 was obtained from the whole plants of Parnassia wightiana, and showed some cytotoxic activities against NB4, MKN-45 and MCF-7 cells at 20 µM[27]. Triptregelines A-J (106–115), regelidine (28), 1α,6β,15-triacetoxy-8α-benzoyloxy-4β-hydroxyl-9α-(3-nicotinoyloxy)-dihydro-β-agarofuran (116), dimacroregeline A-B (117–118) and triptonine A (119) have been isolated from the stems of Tripterygium regelii, and 107, 108, 113 and 116 exhibited weak cytotoxic effects on taxol-resistant A549T with IC50 values ranged from 29.4 to 54.4 µM[28], 118 showed inhibitory effects on the proliferation of human rheumatoid arthritis synovial fibroblast cell (MH7A) at a concentration of 20 µM[29]. Compounds 120–123 were extracted from the stems of Maytenusoblongata [30]. 1-O-Benzoyl-1-deacetyl-4-deoxyalatamine (121) and 1,2-O-dibenzoyl-1,2-deacetyl-4-deoxyalatamine (122) exhibited strong larvicidal activity on the A. aegypti Paea strain with LD50 values of 9.4 (95% CI: 6.5–10.0) and 2.7 µM (95% CI: 1.9–2.9), respectively. Triptersinine U (124), hypoglaunine B (125) together with 26, 32, 33, 43, 44, and 46 were isolated from the roots of Tripterygium wilfordii, but all dihydroagarofuran derivatives didn’t show cytotoxicity against six human tumor celllines (HepG2, Hep3B, Bcap37, U251, MCF-7 and A549) [31]. Neuroprotective triptersinine Z4–Z14 (126–130, 132–137) and euojaponine C (131) have been obtained from the leaves of Tripterygiumwilfordii [32,33], and 126, 127, 129–131 increased cell viability of the okadaic acid-treated PC12 cells from 60.4 23.0% to 72.4 14.1, ± ± 71.5 11.5, 75.7 15.6,81.2 13.1, and 86.2 25.5% at 10 µM, respectively [32]. At 10 µmol/L, ± ± ± ± compounds 132 and 133 showed moderate inhibitory effects on NO production in LPS-induced macrophages with inhibitory rate at 31.2 3.6 and 40.9 4.3 [33]. Two new sesquiterpene pyridine ± ± alkaloids, Chinese bittersweet alkaloid A (138) and Chinese bittersweet alkaloid B (139) were isolated from the rootbarks of Celastrus angulatus [34]. Monimins I (140) and II (141) have been extracted from the leaves of Monimopetalum chinense [35]. Tripteryford C (142) and tripteryford E (143) have been obtained from the leaves of Tripterygium wilfordii, and 142 exhibited the better protective activity against human neuroblastoma SH-SY5Y cell injury induced by H2O2 with 76.63% cell viability comparing with the positive control Trolox (69.84%) at 12.5 µM[36]. Celaspaculin G (144) was purified fromthe seeds of Celastrus paniculatus, and with non lifespan-extending effect on the nematode Caenorhabditis elegans [37]. Molecules 2020, 25, 2485 4 of 32

Table 1. Reported structures ofdihydroagarofuran sesquiterpenoids 1–144.

No Name R1 R2 R3 R4 R5 R6 R7 R8 R9 Type Ref 1 Mekongensine OAc OBz βOAc βOAc OAc OH βOAc OAc H A [17] 2 7-epi-Mekongensine OAc OBz αOAc βOAc OAc OH βOAc OAc H A [17] 3 1-O-Benzoyl-1-deacetylmekongensine OBz OBz βOAc βOAc OAc OH βOAc OAc H A [17] 4 90-Deacetoxymekongensine OAc OBz βOAc βOAc OAc OH βOAc H H A [17] 1-O-Benzoyl-1-deacetyl- 5 OBz OBz βOAc βOAc OAc OH βOAc H H A [17] 90-deacetoxymekongensine 6 7-epi-Euojaponine A OBz OH αOAc βOAc OAc OH βOAc H CH3 B[17] 7 2-O-Benzoyl-2- deacetylmayteine OBz OAc βOAc βOAc OAc OH βOBz H CH3 B[17,24] 8 7-epi-5-O-Benzoyl-5- deacetylperitassine A OAc OBz αOAc βOAc OAc OH βOAc H CH3 C[17] 9 7-epi-Euonymine OAc OAc αOAc βOAc OAc OH βOAc H CH3 B[17] 10 Mayteine OBz OAc βOAc βOAc OAc OH βOAc H CH3 B[17] 11 7-epi-Mayteine OBz OAc αOAc βOAc OAc OH βOAc H CH3 B[17] 12 Euonymine OAc OAc βOAc βOAc OAc OH βOAc H CH3 B[17,18,21,26] 13 90-O-Acetyl-7-deacetoxy- 7-oxowilfortrine OAc OAc O βOAc OAc OH βOFu OAc H A [18,26] 14 90-O-Acetylwilfortrine OAc OAc βOAc βOAc OAc OH βOFu OAc H A [18] 15 90-O-Furanoylwilfordine OAc OAc βOAc βOAc OAc OH βOBz OFu H A [18] 16 7-O-Benzoyl-5,7-dideacetylwilformine OAc OH βOBz βOAc OAc OH βOAc H H A [18] 17 Wilfortrine OAc OAc βOAc βOAc OAc OH βOFu OH H A [18,21,26] 18 Wilforgine OAc OAc βOAc βOAc OAc OH βOFu H H A [18,23,26] 19 Wilfordine OAc OAc βOAc βOAc OAc OH βOBz OH H A [18,26] 20 Wilforine OAc OAc βOAc βOAc OAc OH βOBz H H A [18,26] 21 Wilformine OAc OAc βOAc βOAc OAc OH βOAc H H A [18] 22 Wilforidine OAc OAc βOAc βOAc OAc OH βOH OH H A [18] 23 Cangorinine E-1 OAc OBz βOAc βOAc OAc OH βOAc H CH3 B[18] 24 Ebenifoline E-II OBz OBz βOAc βOAc OAc OH βOAc H CH3 B[18] 25 Neoeuonymine OAc OH βOAc βOAc OAc OH βOAc H CH3 B[18,24,26] 26 Peritassine A OAc OAc βOAc βOAc OAc OH βOAc H CH3 C[18,21,31] 27 Wilfornine G OAc OAc βONic βOAc OAc OH βOAc H CH3 C[18] 28 Regelidine OBz ONic H αOBz H OH HHHD[18,24,28] 9-O-trans-Cinnamoyl- 29 OBz ONic H αOtCin H OH HHHD[18] 9-debenzoylregelidine 1β-Acetoxy-8α,9β-dibenzoyloxy-13- 30 OAc H αOBz βOBz ONic H H H H D [19] nicotinoyloxy-β-dihydroagarofuran Molecules 2020, 25, 2485 5 of 32

Table 1. Cont.

No Name R1 R2 R3 R4 R5 R6 R7 R8 R9 Type Ref 1β,2β-Diacetoxy-9α-benzoyloxy-13- 31 OAc H H αOBz ONic H βOAc H H D [19] nicotinoyloxy-β-dihydroagarofuran 32 Hypoglaunine E OAc OH βOAc βOAc OFu OH βOAc OH CH3 C[20,21,31] 33 Hypoglaunine F OAc OH βOAc βOAc OAc OH βOFu OH CH3 C[20,31] 34 Triptersinine A OtCin OH O βONic OAc OH HHHD[21] 35 Triptersinine B OcCin OH O βONic OAc OH HHHD[21] 36 Triptersinine C βOtCin OH βOAc βONic OAc OH HHHD[21] 37 Triptersinine D OcCin OH βOAc βONic OAc OH HHHD[21] 38 Triptersinine E OcCin OAc βOAc βONic OAc OH HHHD[21] 39 Triptersinine F OAc ONic βOAc βOFu OAc OH HHHD[21] 40 Triptersinine G OAc OAc βONic βOFu OAc OH HHHD[21] 41 Triptersinine H OFu OAc βONic βOFu OAc OH HHHD[21] 42 Triptersinine L OAc ONic βOAc αOTig OAc OH HHHD[21] 43 Wilfordinine A OAc OAc βOAc βOAc OAc OH βOH H CH3 C[21,31] 44 Hypoglaunine A OAc OAc βOAc βOAc OFu OH βOAc OH CH3 C[21,31] 45 Wilfordinine E OAc OAc βOAc βOAc OAc OH βOAc H H F [21] 46 Euonine OAc OAc βOAc βOAc OAc OH βOAc H H A [21,31] 47 Evonine OAc OAc O αOAc OAc OH αOAc H CH3 G[22] 48 Neoevonine OAc OH O αOAc OAc OH αOAc H CH3 G[22] 1β,2β,5α,8β,11-Pentaacetoxy- 49 4α-hydroxy-3α-(2-methylbutanoyl)- OAc OAc O αOAc OAc OH αOAc OMeBu ONic E[22] 15-nicotinoyl-7-oxo-dihydroagarofuran 50 Triptersinine M OtCin OAc βOAc βONic OAc OH HHHD[23] 51 Triptersinine N ONic OFu βOAc βOFu OAc OH HHHD[23] 52 Triptersinine O OFu OFu βOAc βONic OAc OH HHHD[23] 53 Triptersinine P OTig OAc βONic βONic OAc OH HHHD[23] 54 Triptersinine Q OFu OAc βONic βOTig OAc OH HHHD[23] 55 Triptersinine R OAc OAc βONic αOFu OAc OH HHHD[23] 56 Triptersinine S OAc OFu βOAc βONic OAc OH HHHD[23] 57 Triptersinine T OAc OH βOAc βONic OAc H H H H D [23] 58 Tripterygiumine A OAc OAc - βOAc - OH βOBz H CH3 H[24] 59 Tripterygiumine B OAc OAc βOBz βOAc OAc OH βOAc H CH3 B[24] 60 Tripterygiumine C OAc OBz βOAc βOAc OAc OH βOBz H CH3 B[24] 61 Tripterygiumine D OH OBz βOH βOH OH OH βOH H CH3 B[24] 62 Tripterygiumine E OAc OH βOAc βOAc OAc OH βOFu H CH3 B[24] Molecules 2020, 25, 2485 6 of 32

Table 1. Cont.

No Name R1 R2 R3 R4 R5 R6 R7 R8 R9 Type Ref

63 Tripterygiumine F OAc OFu βOAc βOAc OAc OH βOBz H CH3 B[24] 64 Tripterygiumine G OAc OBz βOAc βOAc OAc OH βOFu H CH3 B[24] 65 Tripterygiumine H OH OAc βOH βOH OH OH βOH H CH3 B[24] 66 Tripterygiumine I OAc OH βOAc βOAc OAc OH βOBz H CH3 B[24] 67 Tripterygiumine J OAc OH βOH βOAc OAc OH βOAc H CH3 B[24] 68 Tripterygiumine K OAc OH βOAc βOAc OBz OH βOH H CH3 B[24] 69 Tripterygiumine L ONic OH βOAc βOAc OAc OH βOAc H CH3 B[24] 70 Hyponine D OAc OBz βOAc βOAc OAc OH βONic H CH3 B[24] 71 Hexadesacetyleuomynine OH OH βOH βOH OH OH βOH H CH3 B[24] 72 Euojaponine A OBz OH βOAc βOAc OAc OH βOAc H CH3 B[24] 73 Hyponine C OAc OAc βOAc βOAc OBz OH βOAc H CH3 B[24] 7-Acetyloxy-O11-benzoyl-O2,11- deacetyl-7- 74 OAc OAc βOAc βOAc OBz OH βOH H CH B[24] deoxoevonine 3 75 4-Hydroxy-7-epi-chuchuhuanine E-V OAc OAc βOAc βOAc OAc OH βOH H CH3 B[24,26] 76 Wilfornine F OAc OBz βOAc βOAc OAc OH βOH H CH3 B[24] 77 Tripterygiumine M OAc OH O βOAc OAc OH βOBz H H A [24] 78 Tripterygiumine N OAc OH O βOAc OAc OH βOBz OFu H A [24] 79 Tripterygiumine O OAc OH βOAc βOAc OAc OH βOFu OBz H A [24] 80 Tripterygiumine P OH OAc βOH βOH OH OH βOH OBz H A [24] 81 Tripterygiumine Q OH OAc βOH βOH OH OH βOH OFu H A [24] 82 Triptonine B OAc OAc βOAc βOAc OAc OH βOFu OFu H A [24] 83 1-Desacetylwilforgine OH OAc βOAc βOAc OAc OH βOFu H H A [24] 84 Alatamine OAc OAc O βOAc OAc OH βOBz OH H A [24] 85 Alatusinine OAc OAc βOAc βOAc OAc OH βOAc OH H A [24] 86 Wilforzine OAc OH βOAc βOAc OAc OH βOBz H H A [24] 87 Wilforjine OAc OAc βOAc βOAc OAc OH βOH H H A [24,26] 88 Tripterygiumine R ONic OH H αOBz H OH HHHD[24] 1β,5α,11-Triacetoxy-7β- 89 benzoyl-4α-hydroxy- 8β- OAc OAc βOBz αONic OAc OH HHHD[24] nicotinoyl-dihydroagarofuran 90 Wilforcidine OBz ONic H αOtCin H OH HHHD[24] 5α-Benzoyl-4α-hydroxy- 1β,8α- 91 ONic OBz H αONic H OH HHHD[24] dinicotinoyl-dihydroagarofuran Molecules 2020, 25, 2485 7 of 32

Table 1. Cont.

No Name R1 R2 R3 R4 R5 R6 R7 R8 R9 Type Ref 1α,2α,6β,8β,9α,15-Hexacetoxy- 4β-hydroxy-3β,13-[2 - 92 0 OAc OAc βOAc αOAc OAc OH αOAc H H I [25] (3-carboxybutyl)]nicotinic acid-dicarbolactone-β-di hydroagarofuran 1α,2α,9α,15-Tetracetoxy- 4β,6β-dihydroxy- 8-oxo,3β,13-[4 - 93 0 OAc OH O βOAc OAc OH αOAc H H J [25] (3-carboxybutyl)]nicotinicacid- dicarbolactone- β-dihydroagarofuran 1α,2α,9α,15-Tetracetoxy- 4β,6β,8β-trihydroxy-3β,13-[4 - 94 0 OAc OH βOH βOAc OAc OH αOAc H H J [25] (3-carboxybutyl)]nicotinic acid- dicarbolactone- β-dihydroagarofuran 1α,2α,8β,9α,15-Pentacetoxy- 4β,6β-dihydroxy-3β,13- 95 OAc OH βOAc βOAc OAc OH αOAc H H J [25] [40-(3-carboxybutyl)]nicotinic acid-dicarbolactone-β- dihydroagarofuran 96 Tripterygiumine S OAc OAc O βOAc OAc OH βOH OFu H A [26] 97 Tripterygiumine T OAc OH O βOAc OAc OH βOH OH H A [26] 98 Tripterygiumine U OAc OAc O βOAc OAc OH βOH H H A [26] 99 Tripterygiumine V OAc OAc βOAc βOAc OAc OH βOH OBz H A [26] 100 Tripterygiumine W OFu OBz βOAc βOAc OAc OH βOH H CH3 B[26] 101 Wilfornine A OAc OAc βOAc βOAc OAc OH βOAc OBz H A [26] 102 Wilfornine D OAc OAc βOAc βOAc OAc OH βOAc OFu H A [26] 103 Tripfordine A OAc OAc βOAc βOAc OAc OH βOH OH H A [26] 104 2-Debenzoyl-2-nicotinoylwilforine OAc OAc βOAc βOAc OAc OH βONic HHA[26] (+)-(1R,2S,4S,5S,6R,7R,9S,10R)- 105 1,2,15-Triacetoxy-9-benzoyloxy-6- OAc ONic H βOBz OAc OH αOAc H H E [27] nicotinoyloxydihydro-β-agarofuran 106 Triptregeline A ONic OH βOAc αOBz OAc OH αOAc H H E [28] 107 Triptregeline B ONic OAc αOAc αOBz OAc OH HHHE[28] 108 Triptregeline C ONic OAc αOH αOBz OH OH HHHE[28] 109 Triptregeline D OFu OAc αONic αOBz OAc OH HHHE[28] 110 Triptregeline E OFu OH αONic αOBz OAc OH HHHE[28] 111 Triptregeline F OAc OH αONic αOBz OAc OH HHHE[28] 112 Triptregeline G OFu OH αONic αOAc OAc OH HHHE[28] Molecules 2020, 25, 2485 8 of 32

Table 1. Cont.

No Name R1 R2 R3 R4 R5 R6 R7 R8 R9 Type Ref 113 Triptregeline H OBz OAc αOH αONic OAc OH HHHE[28] 114 Triptregeline I OFu ONic H βOBz H OH βOAc H H E [28] 115 Triptregeline J OBz ONic H βOBz H OH HHHE[28] 1α, 6β, 15-Triacetoxy-8α-benzoyloxy- 116 4β-hydroxyl -9α-(3-nicotinoyloxy)- OAc OAc αOBz αONic OAc OH HHHE[28] dihydro-β-agarofuran 117 Dimacroregeline A OH OAc H αOH - OH αOH H CH3 K[29] 118 Dimacroregeline B OH OAc OAc αOH - OH αOH H CH3 K[29] 119 Triptonine A OAc OAc - αOAc - OH αOAc H CH3 L[29] 120 4-Deoxyalatamine OAc OAc O αOAc OAc H αOAc OH H I [30] 121 1-O-Benzoyl-1-deacetyl-4-deoxyalatamine OBz OAc O αOAc OAc H αOAc OH H I [30] 1, 2-O-Dibenzoyl-1, 122 OBz OAc O αOAc OAc H αOBz OH H I [30] 2-deacetyl-4-deoxyalatamine 123 4-Deoxyisowilfordine OAc OAc βOAc αOAc OAc H αOBz OH H J [30] 124 Triptersinine U OAc OAc βOAc βOAc OAc OH βOAc αONic ONic D[31] 125 Hypoglaunine B OAc OAc βOAc βOAc OFu OH βOAc OH CH3 C[31] 126 Triptersinine Z4 OFu OAc βOAc βONic OAc H H H H D [32] 127 Triptersinine Z5 OAc OFu βOAc βONic OAc H H H H D [32] 128 Triptersinine Z6 OFu OFu βOAc βONic OAc H H H H D [32] 129 Triptersinine Z7 OcCin OAc βOAc βONic OAc H H H H D [32] 130 Triptersinine Z8 OtCin OAc βOAc βONic OAc H H H H D [32] 131 Euojaponine C OBz OBz βOAc βOAc OAc OH βOH H CH3 B[32] 132 Triptersinine Z9 OcCin OFu βOAc βONic OAc OH HHHD[33] 133 Triptersinine Z10 OtCin OFu βOAc βONic OAc OH HHHD[33] 134 Triptersinine Z11 OtCin OAc βONic βOFu OAc OH HHHD[33] 135 Triptersinine Z12 OcCin OAc βONic βOFu OAc OH HHHD[33] 136 Triptersinine Z13 ONic OFu βOAc βOTig OAc OH HHHD[33] 137 Triptersinine Z14 OAc OFu βONic βOTig OAc OH HHHD[33] 138 Chinese bittersweet alkaloid A OAc OAc βOAc βOAc OiBu OH βOH H CH3 B[34] 139 Chinese bittersweet alkaloid B OAc OAc βOAc βOAc OiBu OH βOAc H CH3 B[34] 140 Monimin I ONic ONic H αOAc H H H H H E [35] 141 Monimin II ONic ONic αOH αOBz H H H H H E [35] 142 Tripteryford C ONic OH βOAc αOAc OAc H αOAc βOH H E [36] 143 Tripteryford E ONic OAc αOH βOFu OAc OH αOAc βOH H E [36] 144 Celaspaculin G OAc OBz βOAc αONic H OH HHHE[37] Molecules 2020, 25, 2485 9 of 32 Molecules 2020, 25, x FOR PEER REVIEW 4 of 31

FigureFigure 1. Twelve 1. Twelve types types (A (A–L–L)) of of dihydroagarofurandihydroagarofuran sesquiterpenoid sesquiterpenoid skeletons. skeletons.

2.2. Drimane and Friedo-Drimane Sesquiterpenoids Nitrobenzoyl drimane sesquiterpenoids are rare in natural sources, Aspergillus fungi species being the only known sources.6β,9α-Dihydroxy-14-p-nitrobenzoylcinnamolide (145) and insulicolide A (146), insulicolide B (147), 14-O-acetylinsulicolide A (148), insulicolide C (149) and 9- deoxyinsulicolide A (150) (Figure 2) were isolated from extracts of the culture of marine-derived fungus Aspergillus ochraceus Jcma1F17 [38,39]. All of them displayed significant cytotoxicity against 10 human cancer celllines (H1975, U937, K562, BGC-823, Molt-4, MCF-7, A549, Hela, HL60, and Huh- 7), with IC50 values ranging from 1.95 mM to 6.35 mM, and 145 also exhibited moderate inhibitory Moleculesactivity 2020against, 25, 2485two viruses, H3N2 and EV71, with IC50 values of 17.0 and 9.4 mM, respectively [38]. 10 of 32 Compound 146 showed the strongest activities, with IC50 values of 1.5, 1.5, and 0.89 μM, against ACHN, OSRC-2, and 786-O cells, respectively [39]. 148 indicated potent inhibitory activities atlowμM (advancedlevels, comparable renal cell to carcinoma)the positive [control,39]. Additionally, sorafenib, adrug145 and (Nexavar)148 exhibited approved stronger for the treatment cytotoxicity of to 786-O cellsprimary (IC50 kidneycancer4.3 and 2.3 µ(advancedM, respectively) renal cell than carcinoma) to OS-RC-2 [39]. (IC Additionally,50 8.2 and 5.3 145µM, and respectively) 148 exhibited and ACHN (ICstronger50 11 andcytotoxicity 4.1 µM, to respectively)786-O cells (IC [5039 4.3]. and Purpuride 2.3 μM, respectively) (151), berkedrimane than to OS-RC-2 B (152 (IC),50 minioluteumides 8.2 and A–D5.3 μ (M,153 respectively), 154, 156 and and157) ACHN, purpuride (IC50 11 Band (155 4.1) (FigureμM, respectively)2) featuring [39]. with Purpuride lactones conjugated(151), a Nberkedrimane-acetyl-L-valine, B (152 and), minioluteumides such drimane sesquiterpenoid A–D (153, 154, 156 are and rare 157) in nature,, purpuride which B ( were155) (Figure extracted 2) from the marinefeaturing fungus, with lactonesTalaromyces conjugated minioluteus a N-acetyl-L-valine,(Penicillium and minioluteum such drimane)[40 sesquiterpenoid]. Compounds are152 rare, 153 in and 157 nature, which were extracted from the marine fungus, Talaromycesminioluteus (Penicillium minioluteum) exhibited cytotoxic activity with IC50 values of 193.3, 50.6 and 57.0 µM against HepG2 cancer cell line, [40]. Compounds 152, 153 and 157 exhibited cytotoxic activity with IC50 values of 193.3, 50.6 and 57.0 respectively [40]. A new sesquiterpene lactonepurpuride D (158), berkedrimane A (159), along with μM against HepG2 cancer cell line, respectively [40]. A new sesquiterpene lactonepurpuride D (158), 151, 152, 155, 157 (Figure2) were prepared from a culture of marine-sourced fungus Penicillum ZZ1283 berkedrimane A (159), along with 151, 152, 155, 157 (Figure 2) were prepared from a culture of inmarine-sourced the medium fungus of potato Penicillum dextrose ZZ1283 broth in was the medium found to of havepotato antimicrobial dextrose broth activities was found with to have MIC values ofantimicrobial 4–14 µg/mL activities against with MRSA MIC [ 41values]. Saccharoquinoline of 4–14 μg/mL against (160 MRSA) (Figure [41].2) Saccharoquinoline composing of a drimane-type(160) sesquiterpene(Figure 2) composing unit in of combination a drimane-type with sesquiterp anapparentene unit 6,7,8-trihydroxyquinoline-2-carboxylic in combination with anapparent 6,7,8- acid with cytotoxicitytrihydroxyquinoline-2-carboxylic against the HCT-116 acidwithcytoto cancer cell linexicity by against inducing the G1HCT-116 arrest, cancer and was cell obtained line by from the fermentationinducing G1 arrest, broth and of the was marine-derived obtained from the bacterium fermentationSaccharomonospora broth of the marine-derivedsp. CNQ-490 bacterium [42]. Saccharomonosporasp. CNQ-490 [42].

Figure 2. The structures of compounds 145–160. Figure 2. The structures of compounds 145–160. Marine sponges are a rich source of bioactive secondary metabolites, the majority of Marine sponges are a rich source ofbioactive secondary metabolites, the majority of which are whichsesquiterpene are sesquiterpene quinones/hydroquinones, quinones/hydroquinones, most of which possess most either of whichadrimane possess or a rearranged either adrimane4,9- or afriedodrimane rearranged 4,9-friedodrimaneterpenoid skeleton, which terpenoid contains skeleton, a C15 sesquiterpene which contains moiety a C15incorporating sesquiterpene a C6 moiety incorporatingbenzoquinone or a C6hydroquinone benzoquinone group or framework. hydroquinone Drimane group sesquiterpene framework. quinones Drimane represent sesquiterpene a quinoneslarge group represent of biologically a large active group marine of natural biologically products. active Six nitrogenous marine natural drimane products. sesquiterpenoid Six nitrogenous drimaneaminoquinones sesquiterpenoid (Figure 3 and aminoquinones Table 2), named (Figure 18-aminoarenarone3 and Table 2(161), named), 19-aminoarenarone 18-aminoarenarone (162), ( 161), 19-aminoarenarone18-methylaminoarenarone (162), 18-methylaminoarenarone(163), 19-methylaminoarenarone (163), 19-methylaminoarenarone(164), along with two (dimeric164), along with twopopolohuanone dimeric popolohuanone F (165), popolohuanone F (165), A popolohuanone (166) isolated from A the (166 Australian) isolated marine from sponge the Australian Dysidea marine sp., and 165 and 166 showed DPPH radical scavenging activitywith IC50 values of 35.0 and 35.0 μM, sponge Dysidea sp., and 165 and 166 showed DPPH radical scavenging activity with IC respectively [43]. A new sesquiterpene benzoxazole, nakijinol B (167), its acetylated derivative, 50 values of 35.0 and 35.0 µM, respectively [43]. A new sesquiterpene benzoxazole, nakijinol B nakijinol B diacetate (170), and two newsesquiterpene quinones, smenospongines B (168) and C (169) (167(Figure), its 3 acetylatedand Table derivative,2), were extracted nakijinol from B diacetate the methanol (170), andextract two of newsesquiterpenethe marine sponge quinones, smenosponginesDactylospongiaelegans B, (and168 )were and found C (169 to have) (Figure cytotoxic3 and activities Table2 in), the were range extracted of 1.8–46 fromμM against the methanol a extract of the marine sponge Dactylospongia elegans, and were found to have cytotoxic activities in the range of 1.8–46 µM against a panel of human tumor cell lines (SF-268, H460, MCF-7, and HT-29) and a normal mammalian cell line (CHO-K1) [44]. Investigation of the marine sponge Dysideaavara, three bioactive sesquiterpenoid Quinones afforded, ( )-3 -methylaminoavarone (171), − 0 ( )-4 -methylaminoavarone (172) and ( )-N-methylmelemeleone-A (173) (Figure3 and Table2) with − 0 − their moderate protein kinase inhibition, cytotoxicity, inhibition of NFkB-activity and insecticidal activity [45]. Two sesquiterpene aminoquinines (Figure3 and Table2), smenospongine ( 174) and glycinylilimaquinone (175), were isolated from the Fijian marine sponge Hippospongia sp., and displayed lethality at LD50 = 188 and <500 ppm against brineshrimp, respectively [46]. Bioactivity-guided isolation yielded five new sesquiterpene aminoquinones 5-epi-Nakijiquinone S-N (176–180), two new sesquiterpene benzoxazoles 5-epi-Nakijinol C–D (181 and 182) (Figure3 and Table2) isolated from the sponge Dactylospongia metachromia [47]. Compounds 176–180 showed potent cytotoxicity againstthe mouse lymphoma cell line L5178Y with IC50 values ranging from 1.1 to 3.7 µM[47]. When tested in vitro Molecules 2020, 25, 2485 11 of 32 for their inhibitory potential against 16 different protein kinases, compounds 180 and 181 exhibited the strongest inhibitory activity against ALK, FAK, IGF1-R, SRC, VEGF-R2, Aurora-B, MET wt, and NEK6 kinases (IC50 0.97–8.62 µM) [47]. Dysidaminones A-M (183–195) (Figure3 and Table2), thirteen new sesquiterpene aminoquinones, along with six known ones (196–201), were isolated from the South China Sea sponge Dysidea fragilis [48]. Compounds 185, 187, 190, and 192, 196, and 198 showed cytotoxicity against mouse B16F10 melanoma and human NCI-H929 myeloma, HepG2 hepatoma, and SK-OV-3 ovarian cancer cell lines [48]. In addition, these six cytotoxic compounds also exhibited NF-kB inhibitory activity with IC50 values of 0.05–0.27 mM [48]. Four nitrogenous 4,9-friedodrimane-type sesquiterpenoids (202–205) (Figure3 and Table2) were acquired using the oxidative potential of Verongula rigida on bioactive metabolites from two Smenospongia sponges, and the mixture of 204 and 205 suppressed β-cateninresponse transcription (CRT) via degrading β-catenin and exhibited cytotoxic activity on colon cancer cells [49]. Compounds 206–214, together with 174 (Figure3 and Table2) have been obtained from the Marine Sponge Spongiapertusa Esper, and 174, 213, 214 exhibited activities against the human cancer cell lines U937, HeLa, and HepG2, with most potent cytotoxicities to U937 cells with IC50 values of1.5, 2.8, and 0.6µM, respectively [50]. Four sesquiterpene hydroquinones, dactylospongins A–D (215–218), as wellas five sesquiterpene quinones, melemeleones B–E (219–222) and dysidaminone N (223) (Figure3 and Table2) were isolated from the marine sponge Dactylospongia sp., anti-inflammatory evaluation showed that 215–218, and 223 exhibtited potent inhibitory effects on the production of inflammatory cytokines (IL-6, IL-1β, IL-8, and PEG2) in LPS-induced THP-1 cells with IC50 values of 5.1–9.2 µM[51]. A new sesquiterpenoid aminoquinone nakijiquinone V (224), along with smenospongine (174) (Figure3 and Table2) were extracted from an Indonesian marine Dactylospongia elegans sponge [52]. Eleven new nitrogenous meroterpenoids, cinerols A–K (225–235) (Figure3 and Table2), were isolated from the marine sponge Dysideacinerea, 225 and 226 feature a rare 5H-pyrrolo[1,2a]-benzimidazole moiety, while cinerols 227–231 were examples of rare meroterpene benzoxazoles [53]. Six sesquiterpene quinones/hydroquinones (236–240, 210) (Figure3 and Table2) were acquired from the marine sponge Dactylospongia elegans [54]. Compounds 238–240 showed activities against the human cancer cell lines DU145, SW1990, Huh7, and PANC-1 with IC50 values ranging from 2.33 to 37.85 µM[54]. Three cytotoxic sesquiterpenoid quinones (241–243) (Figure3 and Table2) were purified from South ChinaSea sponge Dysidea sp., and displayed various potent cytotoxic activities with IC50 values ranging from 0.93 to 4.61 µM[55]. Two unique nitrogenous sesquiterpene quinone meroterpenoids, dysidinoid B (244) and dysicigyhone A (245) (Figure3 and Table2) were characterized from the marine sponge Dysideaseptosa, and 244) exhibited signifcant anti-inflammatory effect by inhibiting TNF-α and IL-6 generation with IC50 values of 9.15 µM and17.62 µM, respectively [56]. Two nitrogenous merosesquiterpene, 5-epi-nakijiquinone L (246) and 5-epi-smenospongiarine (247) (Figure3 and Table2) were isolated from the sponge Verongula cf. rigida with weak 5α-reductase inhibitory activity [57]. Drimane sesquiterpenoid-indole alkaloids rarely occur in Nature. Only eight compounds were isolated from actinomycete Streptomyces sp. Three hybrid isoprenoid drimane derivatives—indotertine A(248), drimentine F (249) and drimentine G (250) (Figure4)—were a fforded from a reed rhizosphere soil-derived actinomycete Streptomyces sp. CHQ-64 [58]. Compound 250 showed strong cytotoxicity µ against human cancer cells lines with IC500 s down to 1.01 M, while 248 and 249 showed no significant activity [58]. Four new indolo-drimane sesquiterpenes, dixiamycins A (251) and B (252), oxiamycin (253), and chloroxiamycin (254), were isolated from a marine-derived actinomycete Streptomyces sp. and characterized, together with the known compound xiamycin A (255) (Figure4)[ 59]. 251 and 252 are the first examples of atropisomerism of naturally occurring N N-coupled atropo-diastereomers, − with a dimeric indolo-sesquiterpene skeleton and a stereogenic N N axis between sp3-hybridized − nitrogen atoms [59]. The two dimeric compounds 251 and 252 showed better antibacterial activities than the monomers 253–255 with the IC50 values of 4–16 µg/mL against four indicator strains (Escherichia coli ATCC25922, Staphylococcus aureus ATCC 29213, Bacillus subtilis SCSIO BS01 and Bacillus thuringiensis SCSIO BT01) [59]. Molecules 2020, 25, 2485 12 of 32

Molecules 2020, 25, x FOR PEER REVIEW 12 of 31

Molecules 2020, 25, x FOR PEER REVIEW 1 of 31

Drimane sesquiterpenoid-indole alkaloids rarely occur in Nature. Only eight compounds were isolated from actinomycete Streptomycessp. Three hybrid isoprenoid drimane derivatives―indotertine A (248), drimentine F (249) and drimentine G (250) (Figure 4) ― were afforded from a reed rhizosphere soil-derived actinomycete Streptomyces sp. CHQ-64 [58]. Compound 250 showed strong cytotoxicity against human cancer cells lines with IC50′s down to 1.01 μM, while 248 and 249 showed no significant activity [58]. Four new indolo-drimanesesquiterpenes, dixiamycins A (251) and B (252), oxiamycin (253), and chloroxiamycin (254), were isolated from a marine-derived actinomycete Streptomycessp. and characterized, together with the known compound xiamycin A (255) (Figure 4) [59]. 251 and 252 are the first examples of atropisomerism of naturally occurring N−N-coupled atropo-diastereomers, with a dimeric indolo-sesquiterpene skeleton and a stereogenic N−N axis between sp3-hybridized nitrogen atoms [59]. The two dimeric compounds 251 and 252 showed better antibacterial activities than the monomers 253–255 with the IC50 values of 4−16 μg/mL against four indicator strains (Escherichia coli ATCC25922, Staphylococcus aureus ATCC 29213, Figure 3. The friedo-drimane sesquiterpenoidskeletons(I–XXI) and three dimers. Bacillus subtilisFigure SCSIO 3. The BS01 friedo-drimane and Bacillus sesquiterpenoidskeletonsthuringiensis SCSIO BT01) ( I[59].–XXI ) and three dimers. Table 2. Reported structures offriedo-drimane sesquiterpenoids.

No Name R1 R2 R3 R4 R5 R6 R7 Type Ref 161 18-Aminoarenarone H NH2 H αH αCH3 βCH3 βCH3 I [43] 162 19-Aminoarenarone NH2 H H αH αCH3 βCH3 βCH3 I [43] 163 18-Methylaminoarenarone H NHCH3 H αH αCH3 βCH3 βCH3 I [43] 164 19-Methylaminoarenarone NHCH3 H H αH αCH3 βCH3 βCH3 I [43] 167 Nkijinol B OH OH H H βCH3 βCH3 βCH3 II [44] 168 Smenospongine B H NHCH2COOH OH αH βCH3 βCH3 βCH3 I [44] 169 Smenospongine C H NH(CH2)2COOH OH H βCH3 βCH3 βCH3 II [44] 170 Nakijinol B diacetate OAc OAc H αH βCH3 βCH3 βCH3 I [44] 171 (−)-3′-Methylaminoavarone H NHCH3 H αH βCH3 βCH3 βCH3 III [45]

FigureFigure 4. 4.The The structures structures of compounds compounds 248248–255.–255 .

Molecules 2020, 25, 2485 13 of 32

Table 2. Reported structures oﬀriedo-drimane sesquiterpenoids.

No Name R1 R2 R3 R4 R5 R6 R7 Type Ref

161 18-Aminoarenarone H NH2 H αH αCH3 βCH3 βCH3 I[43] 162 19-Aminoarenarone NH2 HH αH αCH3 βCH3 βCH3 I[43] 163 18-Methylaminoarenarone H NHCH3 H αH αCH3 βCH3 βCH3 I[43] 164 19-Methylaminoarenarone NHCH3 HH αH αCH3 βCH3 βCH3 I[43] 167 Nkijinol B OH OH H H βCH3 βCH3 βCH3 II [44] 168 Smenospongine B H NHCH2COOH OH αH βCH3 βCH3 βCH3 I[44] 169 Smenospongine C H NH(CH2)2COOH OH H βCH3 βCH3 βCH3 II [44] Molecules 2020, 25, x FOR PEER REVIEW 13 of 31 Molecules 2020, 25, x FOR170 PEER REVIEWNakijinol B diacetate OAc OAc H αH βCH βCH βCH I[13 of 31 44] Molecules 2020, 25, x FOR PEER REVIEW 3 3 3 13 of 31 171 ( )-3 -Methylaminoavarone H NHCH H αH βCH βCH βCH III [45] − 0 3 3 3 3 172 (−)-4172′-Methylamino-avarone( )-4 -Methylamino-avarone NHCH NHCH3 HHH H αHα H βCHβ3 CHβCH3 βCHβCH3 βCHIII III [45] [45] 172 (−)-4′-Methylamino-avarone0 NHCH3 3 H H αH βCH3 β3CH3 βCH3 3 III3 [45] 172 (−)-4′-Methylamino-avarone− NHCH3 H H αH βCH3 βCH3 βCH3 III [45] 173 (−)-N173-Methylmelemeleone-A( )-N-Methylmelemeleone-A H H N(CHN(CH33)(CH)(CH22)2SO33HHH H αHα H βCHβ3 CHβ3 CH3 βCHβCH3 3 βCHIII3 III [45] [45] 173 (−)-N-Methylmelemeleone-A− H N(CH3)(CH2)2SO3H H αH βCH3 βCH3 βCH3 III [45] 174173 (−)-N174-Methylmelemeleone-ASmenospongineSmenospongine HH N(CH3)(CH NHNH222 )2SO3H OHHOH αHα H βCHβ3 CHβ3 CH3 βCHβCH3 3 βCHIVIII3 [46,50,52]IV [45] [ 46,50,52] 174 Smenospongine H NH2 OH αH βCH3 βCH3 βCH3 IV [46,50,52] 2 3 3 3 175174 Glycinylilimaquinone175SmenospongineGlycinylilimaquinone HH NHCHNH22COOH OH OH αHα H βCHβ3 CHβ3 CH3 βCHβCH3 3 βCHIV3 [46,50,52]IV [46] [46] 175 Glycinylilimaquinone H NHCH2COOH OH αH βCH3 βCH3 βCH3 IV [46] 175 Glycinylilimaquinone H NHCH2COOH OH αH βCH3 βCH3 βCH3 IV [46] 176 5-176epi-Nakijiquinone5-epi-Nakijiquinone S S H H OHOH αHα H αCHα3 CHβCH3 βCHβCH3 βCHV V[ [47] 47] 176 5-epi-Nakijiquinone S H OH αH αCH3 β3CH3 βCH3 3 V3 [47] 176 5-epi-Nakijiquinone S H OH αH αCH3 βCH3 βCH3 V [47]

177 5-epi-Nakijiquinone Q H OH αH αCH3 βCH3 βCH3 V [47] 177 5-177epi-Nakijiquinone5-epi-Nakijiquinone Q Q H H OHOH αH αHαCHα3 CHβCH3 βCHβCH3 βCHV V[ [47] 47] 177 5-epi-Nakijiquinone Q H OH αH αCH3 β3 CH3 βCH3 3 V3 [47]

178 5-epi-Nakijiquinone T H OH αH αCH3 βCH3 βCH3 V [47] 178 5-epi-Nakijiquinone T H OH αH αCH3 βCH3 βCH3 V [47] 178 5-178epi-Nakijiquinone5-epi-Nakijiquinone T T H H OHOH αHα H αCHα3 CHβ3 CH3 βCHβCH3 3 βCHV3 V[ [47] 47]

179 5-epi-Nakijiquinone U H NH(CH2)3SCH 3 OH αH αCH3 βCH3 βCH3 V [47] 179 5-epi-Nakijiquinone U H NH(CH2)3SCH3 OH αH αCH3 βCH3 βCH3 V [47] 179 2 3 3 3 3 3 180 5-179epi-Nakijiquinone5-epi-Nakijiquinone NU U H H NH(CH NH(CH NH(CH2)22CH(CH))3SCH3 3)2 OHOH αHα H αCHα3 CHβ3 CH3 βCHβCH3 3 βCHV3 V[ [47] 47] 180 5-epi-Nakijiquinone N H NH(CH2)2CH(CH3)2 OH αH αCH3 βCH3 βCH3 V [47] 181180 5-180epi5-epi-Nakijiquinone-Nakijinol5-epi-Nakijiquinone C N N OH H H NH(CH NH(CH OCH22))22CH(CH3 3))2 CHOHOH3 αHα H αCHα3 CHβ3 CH3 βCHβCH3 3 βCHVIV3 V[ [47] 47] 181 5-epi-Nakijinol C OH OCH3 CH3 αH αCH3 βCH3 βCH3 VI [47] 3 3 3 3 3 182181 1815-epi-Nakijinol5-epi DC-Nakijinol C CH OH OH3 OCH OCHCH33 CH- CH 3 αHα H αCHα3 CHβ3 CH3 βCHβCH3 3 βCHVIIVI3 VI [47] [47] 182 5-epi-Nakijinol D CH3 CH3 - αH αCH3 βCH3 βCH3 VII [47] 182 5-epi-Nakijinol D CH3 CH 3 - αH α3CH 3βCH 3 βCH VII [47] 183182 Dysidaminone5-epi-Nakijinol DA NHCH CH2CH(CH 3 3)2 CHH 3 H- αH αβCH3 β3 CH3 βCH3 3 VIIIII3 [48][47] 183 Dysidaminone A NHCH2CH(CH3)2 H H αH βCH3 βCH3 βCH3 III [48] 183 Dysidaminone A NHCH2 CH(CH3 ) HH αH β3 CH 3βCH 3 βCH III [48] 184183 Dysidaminone AB NHCH NHCH2CH(CHCH(CH2 3)CH)22CH3 2 3 H H αH βCH3 β3 CH3 βCH3 3 III3 [48] 2 3 2 3 3 3 3 184 184DysidaminoneDysidaminone B B NHCHNHCHCH(CH2CH(CH)CH CH3)CH 2CH3 HHH H αH αHβCHβ CHβ3CH βCHβCH3 βCHIII3 III [48] [48] 185184 Dysidaminone CB NHCH2CH(CH H 3)CH2CH3 N(CHH 3)2 H αH βCH3 βCH3 βCH3 III [48] 185 185DysidaminoneDysidaminone C C H H N(CH33)2 H H αH αHβCHβ3 CHβ3CH3 βCHβCH3 3 βCHIII3 III [48] [48] 186185 Dysidaminone DC N(CH H 3)2 N(CHH 3)2 H αH βCH3 βCH3 βCH3 III [48] 186 186DysidaminoneDysidaminone D D N(CH N(CH3)2 ) HHH H αH αHβCHβ3 CHβCH3 βCHβCH3 βCHIII III [48] [48] 3 32 2 3 3 3 3 3 3 187186 Dysidaminone DE N(CH H ) NHCH2CH(CHH 3)2 H αH βCH3 βCH3 βCH3 III [48] 187 187DysidaminoneDysidaminone E E H H NHCH NHCH22CH(CH3))22 H H αH αHβCHβ3 CHβ3CH3 βCHβCH3 3 βCHIII3 III [48] [48] 188187 Dysidaminone EF H NHCH NHCH2CH(CH2CH(CH3)CH3)22CH 3 H αH βCH3 βCH3 βCH3 III [48] 188 188DysidaminoneDysidaminone F F H H NHCH NHCH22CH(CH33)CH2CHCH33 H H αH αHβCHβ3 CHβ3CH3 βCHβCH3 3 βCHIII3 III [48] [48] 188 Dysidaminone F H NHCH2CH(CH3)CH2CH3 H αH βCH3 βCH3 βCH3 III [48] 189 Dysidaminone G H H αH βCH3 βCH3 βCH3 III [48] 189 Dysidaminone G H H αH βCH3 βCH3 βCH3 III [48] 189 Dysidaminone G H H αH βCH3 βCH3 βCH3 III [48]

190 Dysidaminone H H NHCH3 H αH βCH3 βCH3 βCH3 I [48] 190 Dysidaminone H H NHCH3 H αH βCH3 βCH3 βCH3 I [48] 191190 DysidaminoneDysidaminone HI NHCH H 3 NHCHH 3 H αH βCH3 βCH3 βCH3 I [48] 191 Dysidaminone I NHCH3 H H αH βCH3 βCH3 βCH3 I [48] 3 3 3 3 192191 Dysidaminone JI NHCH H N(CHH 3)2 H αH βCH3 βCH3 βCH3 I [48] 192 Dysidaminone J H N(CH3)2 H αH βCH3 βCH3 βCH3 I [48] 193192 DysidaminoneDysidaminone KJ NHCH2CH(CH H 3)2 N(CHH 3)2 H αH βCH3 βCH3 βCH3 I [48] 193 Dysidaminone K NHCH2CH(CH3)2 H H αH βCH3 βCH3 βCH3 I [48] 2 3 3 3 3 194193 Dysidaminone KL NHCH NHCH2CH(CHCH(CH3)CH)22CH 3 H H αH βCH3 βCH3 βCH3 I [48] 194 Dysidaminone L NHCH2CH(CH3)CH2CH3 H H αH βCH3 βCH3 βCH3 I [48] 194 Dysidaminone L NHCH2CH(CH3)CH2CH3 H H αH βCH3 βCH3 βCH3 I [48] 195 Dysidaminone M H H αH βCH3 βCH3 βCH3 I [48] 195 Dysidaminone M H H αH βCH3 βCH3 βCH3 I [48] 195 Dysidaminone M H H αH βCH3 βCH3 βCH3 I [48]

196 18-Methylaminoavarone H NHCH3 H αH βCH3 βCH3 βCH3 III [48] 196 18-Methylaminoavarone H NHCH3 H αH βCH3 βCH3 βCH3 III [48] 197196 19-Methylaminoavarone18-Methylaminoavarone NHCHH 3 NHCHH 3 H αH βCH3 βCH3 βCH3 III [48] 197 19-Methylaminoavarone NHCH3 H H αH βCH3 βCH3 βCH3 III [48] 198197 19-Methylaminoavarone18-Aminoavarone NHCHH 3 NHH 2 H αH βCH3 βCH3 βCH3 III [48] 198 18-Aminoavarone H NH2 H αH βCH3 βCH3 βCH3 III [48] 2 3 3 3 199198 19-Aminoavarone18-Aminoavarone NHH 2 NHH H αH βCH3 βCH3 βCH3 III [48] 199 19-Aminoavarone NH2 H H αH βCH3 βCH3 βCH3 III [48] 199 19-Aminoavarone NH2 H H αH βCH3 βCH3 βCH3 III [48] 200 18-Phenethylaminoavarone H H αH βCH3 βCH3 βCH3 III [48] 200 18-Phenethylaminoavarone H H αH βCH3 βCH3 βCH3 III [48] 200 18-Phenethylaminoavarone H H αH βCH3 βCH3 βCH3 III [48]

Molecules 2020, 25, x FOR PEER REVIEW 13 of 31

172 (−)-4′-Methylamino-avarone NHCH3 H H αH βCH3 βCH3 βCH3 III [45] Molecules 2020, 25, 2485 14 of 32 173 (−)-N-Methylmelemeleone-A H N(CH3)(CH2)2SO3H H αH βCH3 βCH3 βCH3 III [45] 174 Smenospongine H NH2 OH αH βCH3 βCH3 βCH3 IV [46,50,52] 175 Glycinylilimaquinone H NHCH2COOH OH αTableH 2.βCHCont.3 βCH3 βCH3 IV [46]

176 5-epi-Nakijiquinone S H OH αH αCH3 βCH3 βCH3 V [47] No Name R1 R2 R3 R4 R5 R6 R7 Type Ref

177 5-epi-Nakijiquinone Q 189 Dysidaminone H G OH αHHH αCH3 βCH3 βCH3α H V βCH3 [47]β CH3 βCH3 III [48]

190 Dysidaminone H H NHCH3 H αH βCH3 βCH3 βCH3 I[48] 178 5-epi-Nakijiquinone T 191 Dysidaminone H I NHCH3 OH αHHH αCH3 βCH3 βCH3α H V βCH3 [47]β CH3 βCH3 I[48] 192 Dysidaminone J H N(CH3)2 H αH βCH3 βCH3 βCH3 I[48]

193 Dysidaminone K NHCH2CH(CH3)2 HH αH βCH3 βCH3 βCH3 I[48] 179 5-epi-Nakijiquinone U H NH(CH2)3SCH3 OH αH αCH3 βCH3 βCH3 V [47] 194 Dysidaminone L NHCH2CH(CH3)CH2CH3 HH αH βCH3 βCH3 βCH3 I[48] 180 5-epi-Nakijiquinone N H NH(CH2)2CH(CH3)2 OH αH αCH3 βCH3 βCH3 V [47]

3 3 3 3 3 181 5-epi-Nakijinol C 195 Dysidaminone OH M OCH CH αHHH αCH βCH βCH α H VI βCH3 [47]β CH3 βCH3 I[48] 182 5-epi-Nakijinol D CH3 CH3 - αH αCH3 βCH3 βCH3 VII [47] 183 Dysidaminone A 196 18-Methylaminoavarone NHCH2CH(CH3)2 H H NHCHαH 3βCH3 βCH3 HβCH3α H III βCH3 [48]β CH3 βCH3 III [48] 184 Dysidaminone B 197 NHCH19-Methylaminoavarone2CH(CH3)CH2CH3 NHCHH 3 H αHHH βCH3 βCH3 βCH3α H III βCH3 [48]β CH3 βCH3 III [48] α β β β 185 Dysidaminone C 198 18-Aminoavarone H N(CH H3)2 H α NHH 2 βCH3 βCH3 HβCH3 H III CH3 [48] CH3 CH3 III [48] 199 19-Aminoavarone NH HH αH βCH βCH βCH III [48] 186 Dysidaminone D N(CH3)2 H 2 H αH βCH3 βCH3 βCH3 III 3 [48] 3 3 187 Dysidaminone E H NHCH2CH(CH3)2 H αH βCH3 βCH3 βCH3 III [48] Molecules 2020, 25, x200 FOR PEER18-Phenethylaminoavarone REVIEW H H αH βCH3 βCH3 βCH3 III14 of [3148 ] 188 Dysidaminone F H NHCH2CH(CH3)CH2CH3 H αH βCH3 βCH3 βCH3 III [48]

189 Dysidaminone G H H αH βCH3 βCH3 βCH3 III [48] 201 201 PopolohuPopolohuanoneanone D D HHH H αHαH βCHβCH3 3 ββCHCH33 ββCHCH33 IIIIII [48] [48] 190 Dysidaminone H H NHCH3 H αH βCH3 βCH3 βCH3 I [48]

191 Dysidaminone I NHCH3 H H αH 3βCH3 βCH3 βCH3 3 I 3 [48] 3 3 202 202 (-)-Nakijinol(-)-Nakijinol E E OHOH OCHOCH3 HH CHCH3 βCHβCH3 ββCHCH3 ββCHCH3 IIII [49] [49] 192 Dysidaminone203 J 203(+)-5-epi-Nakijinol(+)-5-epi-Nakijinol H E E N(CH OH OH3) 2 H OCHα OCHH3 3βCH3 βCHH3 H βCH CHCH33 3 αI CHαCH3 3 [48]ββCH CH33 ββCHCH33 IIII [49] [49] 193 Dysidaminone204 K 204 Nakijinone NHCHNakijinone A 2CH(CH A3)2 CHH CH 3 3 H OCHαOCHH3 3βCH3 βCHH3 H βCH CHCH33 3 βI CHβCH3 3 [48]ββCH CH33 ββCHCH33 VIIIVIII [49] [49] 194 Dysidaminone205 L 205 5-epi-Nakijinone NHCH5-epi2CH(CH-Nakijinone A 3)CH A2CH3 CHHCH 3 3 H OCHαOCHH3 3βCH3 βCHH3 H βCH CHCH33 3 αI CHαCH3 3 [48]ββCH CH33 ββCHCH33 VIIIVIII [49] [49] 18-Deoxy-18- 206 18-Deoxy-18-formamidodictyoceratin206 B COOCHCOOCH3 NHCHONHCHO OHOH βHβH αCHαCH3 ααCHCH3 ααCHCH3 IXIX [50] [50] 195 Dysidaminone M H 3 H αH βCH3 βCH3 βCH3 I 3 [48] 3 3 18-Deoxy-18-(2-formamidodictyoceratin B 207 18-Deoxy-18-(2- COOCH3 NHCOCH2OH OH βH αCH3 αCH3 αCH3 IX [50] 196 18-Methylaminoavaronehydroxyacetyl)aminodictyoceratin H B NHCH3 H αH βCH3 βCH3 βCH3 III [48] 207 hydroxyacetyl)aminodictyoceratin COOCH3 NHCOCH2OH OH βH αCH3 αCH3 αCH3 IX [50] 208 N-Methyl-ent-smenospongine H NHCH3 OH βH αCH3 αCH3 αCH3 I [50] 197 19-Methylaminoavarone NHCHB 3 H H αH βCH3 βCH3 βCH3 III [48] 209 N-Methyl-5-epi-smenospongine H NHCH3 OH αH αCH3 βCH3 βCH3 I [50] 198 18-Aminoavarone 208 N-Methyl-ent-smenospongineH NH H2 H NHCHαH 3 βCH3 βCHOH3 βCHβH3 IIIαCH 3 [48]αCH 3 αCH3 I[50] 20-Demethoxy-20- 2 3 3 α 3 α β β 199 19-Aminoavarone210 209 N-Methyl-5-epi-smenospongineNH H H H NHCHNHCHαH 3 β3 CH βCHOH - βCHHα H IIICHβ CH3 3 [48]βCH CH33 βCHCH33 X I[[50,54]50 ] methylaminodactyloquinone20-Demethoxy-20- D 210 H NHCH - αH βCH βCH βCH X[50,54] 200 18-Phenethylaminoavarone20-Demethoxy-20-methylamino-5- methylaminodactyloquinoneH D H αH 3 βCH3 βCH3 βCH3 III 3 [48] 3 3 211 H NHCH3 - αH βCH3 βCH3 βCH3 IV [50] epidactylo-quinone D 20-Demethoxy-20- 212 H NHCH3 - - αCH3 βCH3 βCH3 XI [50] methylaminodactyloquinone B 213 5-epi-Smenospongine H NH2 OH αH αCH3 βCH3 βCH3 IV [50]

214 Smenospongiadine H OH αH βCH3 βCH3 βCH3 IV [50]

215 Dactylospongin A H OH H βH αCH3 αCH3 αCH3 XII [51] 216 Dactylospongin B H OH H αH βCH3 βCH3 βCH3 XIII [51] 217 Dactylospongin C NHCHO H H βH αCH3 αCH3 αCH3 XIV [51] 218 Dactylospongin D NHCHO H H αH βCH3 βCH3 βCH3 XV [51] 219 ent-Melemeleone B NHCH2CH2SO3H H H βH αCH3 αCH3 αCH3 V [51] 220 Melemeleone C H NHCH2CH2SO3H H βH αCH3 αCH3 αCH3 V [51] 221 Melemeleone D NHCH2CH2SO3H H H αH βCH3 βCH3 βCH3 IV [51] 222 Melemeleone E H NHCH2CH2SO3H- αH βCH3 βCH3 βCH3 XVI [51]

223 Dysidaminone N H H αH βCH3 βCH3 βCH3 IV [51]

224 Nakijiquinone V H OH αH βCH3 βCH3 βCH3 IV [52]

225 Cinerol A H OH - αH βCH3 βCH3 βCH3 XVII [53] 226 Cinerol B H OH - αH βCH3 βCH3 βCH3 XVIII [53] 227 Cinerol C H OH H αH βCH3 βCH3 βCH3 VI [53] 228 Cinerol D H OH CH3 αH βCH3 βCH3 βCH3 VI [53] Molecules 2020, 25, x FOR PEER REVIEW 14 of 31

201 Popolohuanone D H H αH βCH3 βCH3 βCH3 III [48]

202 (-)-Nakijinol E OH OCH3 H CH3 βCH3 βCH3 βCH3 II [49] 203 (+)-5-epi-Nakijinol E OH OCH3 H CH3 αCH3 βCH3 βCH3 II [49] 204 Nakijinone A CH3 OCH3 H CH3 βCH3 βCH3 βCH3 VIII [49] 205 5-epi-Nakijinone A CH3 OCH3 H CH3 αCH3 βCH3 βCH3 VIII [49] 206 18-Deoxy-18-formamidodictyoceratin B COOCH3 NHCHO OH βH αCH3 αCH3 αCH3 IX [50] 18-Deoxy-18-(2- 207 Molecules 2020, 25, 2485 COOCH3 NHCOCH2OH OH βH αCH3 αCH3 αCH3 IX [50] 15 of 32 hydroxyacetyl)aminodictyoceratin B Molecules208 2020, 25N, x-Methyl-ent-smenospongine FOR PEER REVIEW H NHCH3 OH βH αCH3 αCH3 αCH3 I 13 [50] of 31 209 N-Methyl-5-epi-smenospongine H NHCHTable 2.3 Cont. OH αH αCH3 βCH3 βCH3 I [50] 20-Demethoxy-20- 172210 (−)-4′-Methylamino-avarone NHCHH 3 NHCHH 3 H - αHα H βCHβCH3 3 βCHβCH3 3 βCHβCH3 3 III X [45][50,54] methylaminodactyloquinoneNo Name D R1 R2 R3 R4 R5 R6 R7 Type Ref 173 (−)-N-Methylmelemeleone-A H N(CH3)(CH2)2SO3H H αH βCH3 βCH3 βCH3 III [45] 20-Demethoxy-20-methylamino-5-20-Demethoxy-20-methylamino- 174211 211Smenospongine HH NHCHNH2 3 OH- - αHα αHH βCHβCHβ3 CH3 βCHβCH3 βCH3 βCHβCH3 β3CH IV IV [46,50,52]IV [50] [50] epidactylo-quinone5-epidactylo-quinone D D 3 3 3 3 175 Glycinylilimaquinone H NHCH2COOH OH αH βCH3 βCH3 βCH3 IV [46] 20-Demethoxy-20-20-Demethoxy-20- 212 212 HH NHCH3 --- - αCHαCH3 3 βCHβCH3 3 βCHβ3CH 3 XI XI [50] [50] 176 methylaminodactyloquinone5-epi-Nakijiquinonemethylaminodactyloquinone S B B H OH αH αCH3 βCH3 βCH3 V [47] 213 epi α α β β 213 5-epi-Smenospongine5- -SmenospongineH H NH2 OHOH αHH αCHCH3 3 βCHCH3 3 βCH3CH 3 IV IV [50] [50]

177214 5-214Smenospongiadineepi-NakijiquinoneSmenospongiadine Q H H OHOHOH αHα αHH αCHβCHβ3 CH3 β3CHβCH3 βCH3 βCH3 βCH3 β3CH V3 IV IV [47] [50] [50]

215 215DactylosponginDactylospongin A AH HOH H H βHH αCHαCH3 3 αCHαCH3 3αCHα3CH 3 XII XII [51] [51] 178216 5-216epiDactylospongin-NakijiquinoneDactylospongin B T B H HOH OHH H αHα αHH αCHβCHβ3 CH3 β3CHβCH3 βCH3 βCH3 βCH3 β3CH V3 XIII XIII [47] [51] [51] 217 217DactylosponginDactylospongin C CNHCHO NHCHO H H H βHH αCHαCH3 3 αCHαCH3 3αCHα3CH 3XIV XIV [51] [51]

218 218DactylosponginDactylospongin D DNHCHO NHCHO H H H ααHH βCHβCH3 3 βCHβCH3 3 βCHβ3CH 3 XV XV [51] [51] 179 5-epi-Nakijiquinone U H NH(CH2)3SCH3 OH αH β αCHα3 βCH3 α βCH3 α V [47] 219 219ent-Melemeleoneent-Melemeleone B B NHCHNHCH2CH2CH2SO2SO3H3H HHHH βHH αCHCH3 3 αCHCH3 3αCH3CH 3 V V[ [51] 51] 180 5-220epi-NakijiquinoneMelemeleone N C H H NH(CH NHCH2)CH2CH(CHSO HH3)2 OH αH βHαCHα3 CHβCH3 αCHβCH3 αCHV V[ [47] 51] 220 Melemeleone C H NHCH22CH2SO33H H βH αCH3 3 αCH3 3αCH3 3 V [51] 181 5-epi-Nakijinol C OH OCH3 CH3 αH αCH3 βCH3 βCH3 VI [47] 221 Melemeleone D NHCH2CH2SO3H HH αH βCH3 βCH3 βCH3 IV [51] 221 Melemeleone D NHCH2CH2SO3H H H αH βCH3 βCH3 βCH3 IV [51] 182 2225-epi-NakijinolMelemeleone D E CH H3 NHCHCH2CH3 2SO3H-- αH αHαCHβ3 CHβ3CH3 βCHβCH3 3 βCHVII3 XVI [47] [51] 222 Melemeleone E H NHCH2CH2SO3H- αH βCH3 βCH3 βCH3 XVI [51] 183 Dysidaminone A NHCH2CH(CH3)2 H H αH βCH3 βCH3 βCH3 III [48] 184 223DysidaminoneDysidaminone B N NHCH2CH(CH H3)CH2CH3 H H H αH αHβCHβ3 CHβCH3 βCHβCH3 βCHIII IV [48] [51] 223 Dysidaminone N H H αH βCH3 3 βCH3 3 βCH3 3 IV [51] 185 Dysidaminone C H N(CH3)2 H αH βCH3 βCH3 βCH3 III [48] 186 Dysidaminone D N(CH3)2 H H αH βCH3 βCH3 βCH3 III [48] 224 224NakijiquinoneNakijiquinone V V H H OHOH ααHH βCHβCH3 βCHβCH3 βCHβ3CH IV IV [52] [52] 187 Dysidaminone E H NHCH2CH(CH3)2 H αH βCH3 β3CH3 βCH3 3 III3 [48] 188 Dysidaminone F H NHCH2CH(CH3)CH2CH3 H αH βCH3 βCH3 βCH3 III [48] 225 225 Cinerol A Cinerol A H H OH - - ααHH βCHβCH3 3 βCHβCH3 3 βCHβ3CH 3XVIIXVII [53] [53] 189226 226DysidaminoneCinerol B GCinerol BH HOH H H- - ααHH βCHβCH3 3 βCHβCH3 3βCHβ3CH 3XVIIIIII XVIII [48][53] [53] Molecules 2020, 25, x FOR PEER REVIEW 15 of 31 227Molecules 2020, 25, x FOR227 PEERCinerol REVIEW C Cinerol CH H OH H H ααHH βCHβCH3 3 βCHβCH3 3 βCHβ3CH 3 VI VI [53]15 of 31 [53 ] 190228 228DysidaminoneCinerol D HCinerol D H H NHCH OH 3 CHHCH 3 3 ααHH βCHβCH3 3 βCHβCH3 3βCHβ3CH 3 VII VI [48][53] [53] 191229 229DysidaminoneCinerol E CinerolI E NHCH H 3 OHH OH H H H CHα CHH 3 βCHβCH3 3 βCHββCHCH3 3 βCHβCHβ3CH 3 I II II [48] [53] [53] 229 Cinerol E H OH H CH3 3 βCH33 βCH3 3 βCH3 3 II [53] 192230 230DysidaminoneCinerol F JCinerol F H H N(CH OH OH3)2 H H H ααHHαH βCHβCH3 3 βCHββCHCH3 3 3βCHβCHβ3CH 3 3 IXIX XIX [48] [53] [53] 230 Cinerol F H OH H αH βCH3 βCH3 βCH3 XIX [53] 193231 231DysidaminoneCinerol G KCinerol G NHCH2CH(CH H 3)2 OHH OH HCH CH 33 ααHHαH βCHβCH3 3 βCHββCHCH3 3 3βCHβCHβ3CH 3 3 IXIX XIX [48] [53] [53] 231 Cinerol G H OH CH3 αH βCH3 βCH3 βCH3 XIX [53] 194 Dysidaminone L NHCH2CH(CH3)CH2CH3 H H αH βCH3 βCH3 βCH3 I [48] 232 232 Cinerol H Cinerol H HHH H αHαH βCH3 ββCHCH3 βCHβCH3 XIVXIV [53] [53] 232 Cinerol H H H αH βCH33 βCH3 3 βCH3 3 XIV [53] 195 Dysidaminone M H H αH βCH3 βCH3 βCH3 I [48]

196233 18-MethylaminoavaroneCinerol I H NHCHH 3 HH αHα H βCHβCH3 3 βCHβCH3 3 βCHβCH3 3 IIIXIV [48] [53] 233 233 Cinerol I Cinerol I HHH H αHαH ββCHCH33 ββCHCH3 3 βCHβCH3 3 XIVXIV [53] [53] 197 19-Methylaminoavarone NHCH3 H H αH βCH3 βCH3 βCH3 III [48]

198234 18-AminoavaroneCinerol J NHCHOH NH H2 H H αHα H βCHβCH3 3 βCHβCH3 3 βCHβCH3 3 IIIXIV [48] [53] 234 Cinerol J NHCHO H H αH βCH3 βCH3 βCH3 XIV [53] 199235 19-AminoavaroneCinerol K NHCOCHNH22CH(CH 3)2 HH H H αHα H βCHβCH3 3 βCHβCH3 3 βCHβCH3 3 IIIXIV [48] [53] 235 Cinerol K NHCOCH2CH(CH3)2 H H αH βCH3 βCH3 βCH3 XIV [53] 20-Demethoxy-20- 200236 18-Phenethylaminoavarone20-Demethoxy-20- HH NH(CH2)2CH(CH3)2 H - αHα H βCHβCH3 3 βCHβCH3 3 βCHβCH3 3 IIIX [48] [54] 236 isopentylaminodactyloquinone D H NH(CH2)2CH(CH3)2 - αH βCH3 βCH3 βCH3 X [54] isopentylaminodactyloquinone D 20-Demethoxy-20- 237 20-Demethoxy-20- H NHCH2CH(CH3)2 - αH βCH3 βCH3 βCH3 X [54] 237 H NHCH2CH(CH3)2 - αH βCH3 βCH3 βCH3 X [54] isobutylaminodactyloquinoneisobutylaminodactyloquinone DD 238 Smenospongiarine H NH(CH2)2CH(CH3)2 OH βH αCH3 αCH3 αCH3 I [54] 238 Smenospongiarine H NH(CH2)2CH(CH3)2 OH βH αCH3 αCH3 αCH3 I [54] 239 Smenospongorine H NHCH2CH(CH3)2 OH βH αCH3 αCH3 αCH3 I [54] 239 Smenospongorine H NHCH2CH(CH3)2 OH βH αCH3 αCH3 αCH3 I [54] 240 Smenospongimine H NHCH3 OH βH αCH3 αCH3 αCH3 I [54] 240 Smenospongimine H NHCH3 OH βH αCH3 αCH3 αCH3 I [54] 241 (+)-19-Methylaminoavarone NHCH3 H H αH βCH3 βCH3 βCH3 V [55] 241 (+)-19-Methylaminoavarone NHCH3 H H αH βCH3 βCH3 βCH3 V [55]

242 (−)-20-Phenethylaminoavarone H H αH βCH3 βCH3 βCH3 V [55] 242 (−)-20-Phenethylaminoavarone H H αH βCH3 βCH3 βCH3 V [55]

243 (−)-20-Methylaminoavarone H NHCH3 H αH βCH3 βCH3 βCH3 V [55] 243 (−)-20-Methylaminoavarone H NHCH3 H αH βCH3 βCH3 βCH3 V [55] 244 Dysidinoid B H H - αH βCH3 βCH3 βCH3 XX [56] 244 Dysidinoid B H H - αH βCH3 βCH3 βCH3 XX [56] 245 Dysicigyhone A H OH CH3 αH βCH3 βCH3 βCH3 XXI [56] 245 Dysicigyhone A H OH CH3 αH βCH3 βCH3 βCH3 XXI [56] 246 5-epi-Nakijiquinone L H NHCH2CH(CH3)CH2CH3 OH αH αCH3 βCH3 βCH3 IV [57] 246 5-epi-Nakijiquinone L H NHCH2CH(CH3)CH2CH3 OH αH αCH3 βCH3 βCH3 IV [57] 247 5-epi-Smenospongiarine H NH(CH2)2CH(CH3)2 OH αH αCH3 βCH3 βCH3 IV [57] 247 5-epi-Smenospongiarine H NH(CH2)2CH(CH3)2 OH αH αCH3 βCH3 βCH3 IV [57]

Molecules 2020, 25, 2485 16 of 32

Table 2. Cont.

No Name R1 R2 R3 R4 R5 R6 R7 Type Ref

234 Cinerol J NHCHO H H αH βCH3 βCH3 βCH3 XIV [53] Molecules 2020, 25, x FOR PEER REVIEW 13 of 31 235 Cinerol K NHCOCH2CH(CH3)2 HH αH βCH3 βCH3 βCH3 XIV [53] 20-Demethoxy-20- 236 H NH(CH2)2CH(CH3)2 - αH βCH3 βCH3 βCH3 X[54] 172 (−)-4′-Methylamino-avaroneisopentylaminodactyloquinone D NHCH3 H H αH βCH3 βCH3 βCH3 III [45] 173 (−)-N-Methylmelemeleone-A20-Demethoxy-20- H N(CH3)(CH2)2SO3H H αH βCH3 βCH3 βCH3 III [45] 237 H NHCH2CH(CH3)2 - αH βCH3 βCH3 βCH3 X[54] 174 Smenospongineisobutylaminodactyloquinone D H NH2 OH αH βCH3 βCH3 βCH3 IV [46,50,52] 238 Smenospongiarine H NH(CH ) CH(CH ) OH βH αCH αCH αCH I[54] 175 Glycinylilimaquinone H NHCH2 22COOH 3 2 OH αH βCH3 β3CH3 βCH3 3 IV3 [46] 239 Smenospongorine H NHCH2CH(CH3)2 OH βH αCH3 αCH3 αCH3 I[54] 240 β α α α 176 5-epi-NakijiquinoneSmenospongimine S H H NHCH3 OHOH αH HαCH3 CHβ3CH3 CHβCH3 3 CHV3 I[ [47] 54] α β β β 241 (+)-19-Methylaminoavarone NHCH3 HH H CH3 CH3 CH3 V[55]

177 5-242epi-Nakijiquinone( )-20-Phenethylaminoavarone Q H H OHH αH αHαCHβ3 CHβ3CH3 βCHβCH3 3 βCHV3 V[ [47] 55] − 243 ( )-20-Methylaminoavarone H NHCH H αH βCH βCH βCH V[55] − 3 3 3 3 178 5-244epi-NakijiquinoneDysidinoid T B H H HOH - αH αHαCHβ3 CHβ3CH3 βCHβCH3 3 βCHV3 XX [47] [56] 245 Dysicigyhone A H OH CH3 αH βCH3 βCH3 βCH3 XXI [56]

246 5-epi-Nakijiquinone L H NHCH2CH(CH3)CH2CH3 OH αH αCH3 βCH3 βCH3 IV [57] 179 5-epi-Nakijiquinone U H NH(CH2)3SCH3 OH αH αCH3 βCH3 βCH3 V [47] 247 5-epi-Smenospongiarine H NH(CH2)2CH(CH3)2 OH αH αCH3 βCH3 βCH3 IV [57] 180 5-epi-Nakijiquinone N H NH(CH2)2CH(CH3)2 OH αH αCH3 βCH3 βCH3 V [47] 181 5-epi-Nakijinol C OH OCH3 CH3 αH αCH3 βCH3 βCH3 VI [47] 182 5-epi-Nakijinol D CH3 CH3 - αH αCH3 βCH3 βCH3 VII [47] 183 Dysidaminone A NHCH2CH(CH3)2 H H αH βCH3 βCH3 βCH3 III [48] 184 Dysidaminone B NHCH2CH(CH3)CH2CH3 H H αH βCH3 βCH3 βCH3 III [48] 185 Dysidaminone C H N(CH3)2 H αH βCH3 βCH3 βCH3 III [48] 186 Dysidaminone D N(CH3)2 H H αH βCH3 βCH3 βCH3 III [48] 187 Dysidaminone E H NHCH2CH(CH3)2 H αH βCH3 βCH3 βCH3 III [48] 188 Dysidaminone F H NHCH2CH(CH3)CH2CH3 H αH βCH3 βCH3 βCH3 III [48]

189 Dysidaminone G H H αH βCH3 βCH3 βCH3 III [48]

190 Dysidaminone H H NHCH3 H αH βCH3 βCH3 βCH3 I [48] 191 Dysidaminone I NHCH3 H H αH βCH3 βCH3 βCH3 I [48] 192 Dysidaminone J H N(CH3)2 H αH βCH3 βCH3 βCH3 I [48] 193 Dysidaminone K NHCH2CH(CH3)2 H H αH βCH3 βCH3 βCH3 I [48] 194 Dysidaminone L NHCH2CH(CH3)CH2CH3 H H αH βCH3 βCH3 βCH3 I [48]

195 Dysidaminone M H H αH βCH3 βCH3 βCH3 I [48]

196 18-Methylaminoavarone H NHCH3 H αH βCH3 βCH3 βCH3 III [48] 197 19-Methylaminoavarone NHCH3 H H αH βCH3 βCH3 βCH3 III [48] 198 18-Aminoavarone H NH2 H αH βCH3 βCH3 βCH3 III [48] 199 19-Aminoavarone NH2 H H αH βCH3 βCH3 βCH3 III [48]

200 18-Phenethylaminoavarone H H αH βCH3 βCH3 βCH3 III [48]

Molecules 2020, 25, 2485 17 of 32

2.3. Eudesmane Sesquiterpenoids Eleven nitrogen-containing eudesmane sesquiterpenoids, halichonadins G–Q (256–266) (Figure5), were isolated from a marine sponge Halichondria sp., and compounds 256 and 258 showed cytotoxicity against murine lymphoma L1210 cells (IC50 5.9 and 6.9 µg/mL)and human epidermoid carcinoma KB cells (IC50 6.7 and 3.4 µg/mL) in vitro, Halichonadin K showed cytotoxicity against human epidermoid carcinoma KB cells (IC50 10.6 µg/mL) in vitro, and halichonadin O displayed antimicrobial activity against Staphylococcus aureus (MIC 8 µg/mL), Micrococcus luteus (MIC 8 µg/mL), and Trichophyton mentagrophytes (IC50 16 µg/mL) [60–62]. One eudesmane-type sesquiterpene, phaeusmane I (267) (Figure5), was isolatedfrom the rhizomes of Curcuma phaeocaulis [63]. Three new nitrogen-containing sesquiterpenoids, the cespilamides C–E (268–270, Figure5) were puriﬁed from the Taiwanese soft coral Cespitularia taeniata, and 270 exhibited cytotoxicity against human breast adenocarcinoma (MCF-7), medulloblastoma (Daoy), and cervical epitheloid carcinoma (Hela) cancer cells with IC50 of 17.5, 22.3, and 24.7 µM, respectively [64]. Acanthine B (271), acanthine C (272), 11-isocyano-7βH-eudesm-5-ene (273), 11-isothiocyano-7βH-eudesm-5-ene (274), and 11-formamido-7βH-eudesm-5-ene (275) (Figure5), were isolated from the Thai sponge Halichondria sp. [65]. Four new uncommon nitrogenous eudesmane-type sesquiterpenes, axiriabilinesMolecules 2020 A–D, 25, x (276 FOR– PEER279), REVIEW and one known related ent-stylotelline (280) (Figure5), were2 isolatedof 31 Axinyssa variabilis fromknown the Hainan related sponge ent-stylotelline (280) (Figurewith 5), no cytotoxicitywere isolated against from severalthe Hainan cancer sponge cells [66]. AxiriabilineAxinyssavariabilis A (276) and with 11-formamido-7 no cytotoxicity againstβH-eudesm-5-ene several cancer (281 cells) (Figure [66]. Axiriabiline5) were extracted A (276) and from 11- South Chinaformamido-7 Sea NudibranchsβH-eudesm-5-enePhyllidiella (281sp.) [(Figure67]. Spiroalanpyrroids 5) were extracted Afrom (282 South) and China B (283 Sea), two Nudibranchs sesquiterpene alkaloidsPhyllidiella withsp an [67]. unprecedented Spiroalanpyrroids eudesmanolide-pyrrolizidine A (282) and B (283), two spirosesquiterpene [55] framework, alkaloids werewith isolatedan togetherunprecedented with two eudesmanolide-pyrrolizidine new sesquiterpene-amino spiro acidadducts, [55] framework, helenalanprolines were isolated together A (284 )with and two B (285) (Figurenew5), sesquiterpene-amino from the roots of acidadInuladucts, helenium helenalanprolines[68]. Bioassays A (284 showed) and B that (285284) (Figureand 2855), fromsigniﬁcantly the roots of Inula helenium [68]. Bioassays showed that 284 and 285 significantly inhibited nitric oxide inhibited nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 valuesproduction of 15.8 and in lipopolysaccharide-ind 13.5 µM, respectivelyuced [68 ].RAW 264.7 macrophages with IC50 values of 15.8 and 13.5 μM, respectively [68].

OCH R O 3 O O O O O O O H OH H H H H H H H N N N NH N N N N N N NH N H H H H H H H H O O R2 256 257 258 259 OH 260 R1=OCH3;R2=H OCH3 261 R1=NHCH2CH2Ph; R2=H OCH3 OMe O O 264 R1=NHCH2CH2Ph; R2=OH O O O N O O O O OH H H H H H H H N N H H N N H NH N NH N NH N H O HN H O O OMe HO H 262 OH 263 266 265 267 H H O O CN O O R H H H H N SCN NHCHO N HN 278 279 281 O 282 O 283 N H H O N O O O H O O H H 268 R-H H H N H R N 269 R=OH R R 270 273 R=NCS 276 R=NHCHO O O 271 R=NCS 274 R=NHCHO 277 R=CN OMe OMe 272 R=NHCHO 275 R=NC 280 R=NC 284 285 FigureFigure 5. 5.The The structures structures of compounds compounds 256256-285.–285 .

2.4. Cadinane2.4. Cadinane Sesquiterpenoids Sesquiterpenoids TwoTwo nitrogenous nitrogenous cadinane cadinane sesquiterpenes sesquiterpenes (3S*, 5 5RR*,*, 6 6RR*,*, 9R 9*)-3-formamido-1(10)-cadineneR*)-3-formamido-1(10)-cadinene (286) (286) and (and)-halichamine (−)-halichamine (287 (287) (Figure) (Figure6) 6) were were isolated isolated fromfrom thethe Thai marine marine sponge sponge HalichondriaHalichondriasp [69].sp. [69]. − CompoundCompound286 showed286 showed moderate moderate cytotoxic cytotoxic activity activity against against HeLa, HeLa, MOLT-3, MOLT-3, and and HepG2HepG2 cellcell lineslines with with IC50 valued of 32.1, 33.4, and 16.0 mM, respectively, while compound287 also displayed IC50 valued of 32.1, 33.4, and 16.0 mM, respectively, while compound 287 also displayed moderate moderate cytotoxic activity against HuCCA-1, MOLT-3, HepG2, and MDA-MB231 cell lines with IC50 cytotoxic activity against HuCCA-1, MOLT-3, HepG2, and MDA-MB231 cell lines with IC valued of valued of 20.3, 34.6, 19.9, and 22.6 mM, respectively [69]. (1R, 6S, 7S, 10S)-10-isothiocyanato-4-50 20.3,amorphene 34.6, 19.9, and(288 22.6), axinisothiocyanate mM, respectively J [(28969].) (1(FigureR, 6S, 6) 7S ,were 10S)-10-isothiocyanato-4-amorphene extracted from the marine sponge (288), Axinyssasp [70]. Halichon C (290) and 4-epihalichon C (291), halichon D (292), halichonG (293), (−)- 10-isocyano-4-cadinene (294), and (−)-10-isothiocyanato-4-cadinene (295) (Figure 6), were obtained from the Thai sponge Halichondriasp [65]. Compounds 290, 291, and 294 exhibited moderate cytotoxicity (IC50 20.9, 29.0, and 9.1 μM, respectively) against the MOLT-3 cell line and compound 292 also showed moderate cytotoxicity against HepG2 and MDA-MB-231 cell lines with IC50 values of 24.3 and 19.3 μM, respectively [65]. New stereoisomers of (+)-(1S*, 4S*, 6S*, 7R*)-4-Isocyano-9- amorphene (296) and of (−)-(1S*, 6R*, 7R*, 10S*)-10-isocyano-4-amorphene (297), 4α-isocyano-9- amorphene (298), (1S*, 4S*, 6S*, 7R*)-4-thiocyanate-9-cadinene (299), (−)-10-isocyano-4-amorphene (300), (−)-10-isothiocyanato-4-cadinene (301) (Figure 6), were identified from Phyllidiella pustulosa and from Phyllidiaocellata [71]. A novel sesquiterpenoidal lactam, commipholactam A (302) (Figure 6) was isolated from Resinacommiphora [72]. Biological assessment against human cancer cells showed that the IC50 values of 302 against HepG2 and A549 cells were 21.73 μM and 128.50 μM, respectively [72]. Axidaoisocyanate A (303), 10-isothiocyanato-4-cadinene (304), 10-formamido-4-cadinene (305), along with 289, 293 (Figure 6), were identified from two South China Sea Nudibranchs Phyllidiella pustulosa, Phyllidiacoelestis [67].

Molecules 2020, 25, 2485 18 of 32 axinisothiocyanate J (289) (Figure6) were extracted from the marine sponge Axinyssa sp. [70]. Halichon C (290) and 4-epihalichon C (291), halichon D (292), halichonG (293), ( )-10-isocyano-4-cadinene − (294), and ( )-10-isothiocyanato-4-cadinene (295) (Figure6), were obtained from the Thai sponge − Halichondria sp. [65]. Compounds 290, 291, and 294 exhibited moderate cytotoxicity (IC50 20.9, 29.0, and 9.1 µM, respectively) against the MOLT-3 cell line and compound 292 also showed moderate cytotoxicity against HepG2 and MDA-MB-231 cell lines with IC50 values of 24.3 and 19.3 µM, respectively [65]. New stereoisomers of (+)-(1S*, 4S*, 6S*, 7R*)-4-Isocyano-9-amorphene (296) and of ( )-(1S*, 6R*, 7R*, 10S*)-10-isocyano-4-amorphene (297), 4α-isocyano-9-amorphene − (298), (1S*, 4S*, 6S*, 7R*)-4-thiocyanate-9-cadinene (299), ( )-10-isocyano-4-amorphene (300), − ( )-10-isothiocyanato-4-cadinene (301) (Figure6), were identiﬁed from Phyllidiella pustulosa and − from Phyllidia ocellata [71]. A novel sesquiterpenoidal lactam, commipholactam A (302) (Figure6) was isolated from Resina commiphora [72]. Biological assessment against human cancer cells showed that the IC50 values of 302 against HepG2 and A549 cells were 21.73 µM and 128.50 µM, respectively [72]. Axidaoisocyanate A (303), 10-isothiocyanato-4-cadinene (304), 10-formamido-4-cadinene (305), along with 289, 293 (Figure6), were identiﬁed from two South China Sea Nudibranchs Phyllidiella pustulosa, Phyllidia coelestis [67]. Molecules 2020, 25, x FOR PEER REVIEW 3 of 31

FigureFigure 6. 6.The The structuresstructures of compounds compounds 286286–305.–305 .

2.5. Bisabolane2.5. Bisabolane Sesquiterpenoids Sesquiterpenoids BrasilamidesBrasilamides E–J (E–J306 (–306311-311), bisabolane), bisabolane sesquiterpenoids sesquiterpenoids with with 3-cyclohexylfuran3-cyclohexylfuran ( (306306 andand 307307) ) and 3-cyclohexylfuranoneand 3-cyclohexylfuranone (308–311 (308) skeletons–311) skeletons (Figure (Figure7), were 7), isolated were isolat fromed scaled-upfrom scaled-up fermentation fermentation cultures of thecultures plant endophyticof the plant fungusendophyticParaconiothynium fungus Paraconiothyniumbrasiliense brasiliense Verkley Verkley [73]. Compound [73]. Compound307 selectively 307 selectively inhibited the proliferation of the breast (MCF-7) and gastric (MGC) cancer cell lines, with inhibited the proliferation of the breast (MCF-7) and gastric (MGC) cancer cell lines, with IC50 values IC50 values of 8.4 and 14.7 μM, respectively [73]. N,N’-bis[(6R,7S)-7-amino-7,8-dihydro-a-bisabolen- of 8.4 and 14.7 µM, respectively [73]. N,N’-bis[(6R,7S)-7-amino-7,8-dihydro-a-bisabolen-7-yl]urea 7-yl]urea (304), and (6R,7S)-7-amino-7,8-dihydro-α-bisabolene (313) (Figure 7), were purified from α (304),the and marine (6R,7 spongeS)-7-amino-7,8-dihydro- Axinyssa sp. collected-bisabolene atIriomote Island (313) [70]. (Figure Compound7), were 312 puriﬁed was the from most thepotent marine spongeinhibitorAxinyssa of PTP1Bsp. collected activity (IC atIriomote50 = 1.9 μM) Island without [70 ].cytotoxicity Compound at 50312 μMwas in two the human most potent cancer inhibitorcell of PTP1Blines, activityhepatoma (IC Huh-750 = 1.9andµ bladderM) without carcinoma cytotoxicity EJ-1 cells at [70]. 50 µ CompoundM in two human312 also cancer moderately cell lines, hepatomaenhanced Huh-7 the andinsulin-stimulated bladder carcinoma phosphorylation EJ-1 cells [ 70levels]. Compound of Aktin 312Huh-7also moderatelycells [70]. D enhanced7,14-3- the insulin-stimulatedisocyanotheonellin ( phosphorylation314) and 3-isocyanotheonellin levels of Aktin (315 Huh-7), theonellin cells [formamide70]. D7,14-3-isocyanotheonellin (316), theonellin (314)isothiocyanate and 3-isocyanotheonellin (317), and 7-isocyano-7,8-dihydro- (315), theonellinα formamide-bisabolene (318316)), (Figure theonellin 7) were isothiocyanate extracted from (317), and 7-isocyano-7,8-dihydro-the two South China Sea nudibranchsα-bisabolene Phyllidiellapustulosa (318) (Figure7) were and Phyllidiacoelestis extracted from [67]. the twoCompounds South China 315, Sea 317, and 318 exhibited strong cytotoxicity against human cancercell line SNU-398 with IC50 values of 0.50, 2.15, and 0.50 μM, respectively [67]. In addition, compound 315 also displayed broad cytotoxicity against the other three cancer cell lines, including A549, HT-29, and Capan-1, with IC50 values of 8.60, 3.35, and 1.98 μM, respectively [67]. A rearranged bisabolene-type sesquiterpene, halichonic acid (319), was isolated from a marine sponge Halichondria sp., together with313 [74] (Figure 7). Compound 313 was cytotoxic against HeLa cells with an IC50 value of 50 μM, whereas 314 did not show cytotoxicity even at 50 μM [74]. Five novel highly oxygenated norbisabolane sesquiterpene, namely phyllanthacidoid U (320), phyllanthacidoidA (321),phyllanthacidoid B (322), phyllanthacidoid L (323), and phyllanthacidoid S (324) (Figure 7) were isolated from the roots and stems of Phyllanthus acidus, and compounds 321–323 displayed potential anti hepatitis B virus (anti- HBV) activities [75].

Molecules 2020, 25, 2485 19 of 32 nudibranchs Phyllidiella pustulosa and Phyllidia coelestis [67]. Compounds 315, 317, and 318 exhibited strong cytotoxicity against human cancercell line SNU-398 with IC50 values of 0.50, 2.15, and 0.50 µM, respectively [67]. In addition, compound 315 also displayed broad cytotoxicity against the other three cancer cell lines, including A549, HT-29, and Capan-1, with IC50 values of 8.60, 3.35, and 1.98 µM, respectively [67]. A rearranged bisabolene-type sesquiterpene, halichonic acid (319), was isolated from a marine sponge Halichondria sp., together with 313 [74] (Figure7). Compound 313 was cytotoxic against HeLa cells with an IC50 value of 50 µM, whereas 314 did not show cytotoxicity even at 50 µM[74]. Five novel highly oxygenated norbisabolane sesquiterpene, namely phyllanthacidoid U (320), phyllanthacidoidA (321),phyllanthacidoid B (322), phyllanthacidoid L (323), and phyllanthacidoid S (324) (Figure7) were isolated from the roots and stems of Phyllanthus acidus, and compounds 321–323 displayed potential anti hepatitis B virus (anti-HBV) activities [75]. Molecules 2020, 25, x FOR PEER REVIEW 4 of 31

FigureFigure 7. 7.The The structures structures of compounds 306306–324.–324 .

2.6. Germacrane,2.6. Germacrane, Elemaneand Elemaneand Iresane Iresane Sesquiterpenoids Sesquiterpenoids TwoTwo germacrane-type germacrane-type sesquiterpenoid sesquiterpenoid dimers—isobisparthenolidine dimers―isobisparthenolidine (325) and bisparthenolidine(325) and (326)bisparthenolidine (Figure8) were isolated (326) (Figure from the 8) chloroform-soluble were isolated from fraction the chloroform-soluble of the methanolic fraction extract ofof thethe bark of Magnoliamethanolic kobus extract(Magnoliaceae) of the bark of [76 Magnolia]. Compound kobus (Magnoliaceae)325 displayed [76]. broad Compound cytotoxicity 325 displayed against four broad cancer cytotoxicity against four cancer cell lines, including A549, SK-OV-3, SK-MEL-2, and HCT-15, with cell lines, including A549, SK-OV-3, SK-MEL-2, and HCT-15, with IC50 values of 2.0, 1.9, 3.9 and 3.2 µM, IC50 values of 2.0, 1.9, 3.9 and 3.2 μM, respectively [76]. Noveliresane sesquiterpene alkaloids, respectively [76]. Noveliresane sesquiterpene alkaloids, halichonines A (327), B (328), and C (329) halichonines A (327), B (328), and C (329) (Figure 8), were identified from the marine sponge (FigureHalichondriaokadai8), were identiﬁed Kadota, from and the marine328 wasthen sponge subjectedHalichondria to the trypan okadai Kadota,blue dye and exclusion328 wasthen using HL60 subjected to thehuman trypan leukemia blue dye cells, exclusion and showed using cytotoxicity HL60 human (IC50 leukemiavalue: 0.60cells, μg/mL) and [77]. showed One γ-elemene-type cytotoxicity (IC 50 value:sesquiterpenes, 0.60 µg/mL) [778β].(H One)-elema-1,3,7(11)-trien-8,12-lactamγ-elemene-type sesquiterpenes, (330) 8β(Figure(H)-elema-1,3,7(11)-trien-8,12-lactam 8) was obtained from the (330)rhizomes (Figure8 )of was Curcuma obtained phaeocaulis from the [63]. rhizomes Three ofnew Curcuma germacrane phaeocaulis sesquiterpenoid-typealkaloids [ 63]. Three new germacrane with sesquiterpenoid-typealkaloidsan unusual Δ8-7,12-lactam moiety, with an glechomanamides unusual ∆8-7,12-lactam A–C (331 moiety,glechomanamides–333) (Figure 8) were isolated A–C from (331– 333) (FigureSalviascapiformis8) were isolated [78]. In from a tubeSalvia formation scapiformis assay, 332[78 showed]. In a the tube most formation potent antiangiogenic assay, 332 showedactivity the in primary screening, and its IC50 value was determined to be 40.4 μM [78]. In addition to VEGFR2, most potent antiangiogenic activity in primary screening, and its IC50 value was determined to be 332 decreased BMP4 expression, which regulates tube formation, and glycolysisrelated proteins, 40.4 µM[78]. In addition to VEGFR2, 332 decreased BMP4 expression, which regulates tube formation, including GLUT1 and HK2, which suggests that the novel compound 332 is worthy of additional and glycolysisrelated proteins, including GLUT1 and HK2, which suggests that the novel compound investigation for angiogenesis-associated pathological conditions [78]. Onopornoids A–D (334–337) 332 is(Figure worthy 8), of three additional elemanes investigation and one germacrane, for angiogenesis-associated were extracted from pathologicalthe whole aerial conditions parts of [78]. OnopornoidsOnopordumalexandrinum A–D (334–337, which) (Figure possess8), three unique elemanes structures and combining one germacrane, a sesquiterpenoid were extractedframework from the wholewith an aerial amino parts acid, L of-prolineOnopordum [79]. alexandrinum, which possess unique structures combining a sesquiterpenoid framework with an amino acid, L-proline [79]. 2.7. Farnesane, Spiroaxane, AromadendraneandPupukeanane Sesquiterpenoids Chemical investigation of the endophytic fungus Emericella sp. (HK-ZJ) isolated from the mangrove plant Aegicerascorniculatum led to the isolation of six farnesane sesquiterpenoids named emeriphenolicins A–F (338–343) (Figure 9) with moderate anti-influenza A viral (H1N1) activities [80]. An unusual farnesane natural product (dotofide, 344) (Figure 9), in which the terpenoid skeleton is interrupted by a guanidine moiety was obtained from the marine slug Doto pinnatifida [81]. Two spiroaxane sesquiterpenes, (−)-axisonitrile-3 (345), (+)-axamide-3 (346), and one aromadendrane sesquiterpene axamide-2 (347) (Figure 9) were isolated from the Thai marine sponge Halichondriasp, and only 345 showed strong activity to the HepG2 cell line withan IC50 value of 1.3 μM [69]. Fasciospyrinadine (348) (Figure 9), a novel farnesane sesquiterpene pyridine alkaloid was extracted froma Guangxi sponge Fasciospongiasp [82].

Molecules 2020, 25, 2485 20 of 32

2.7. Farnesane, Spiroaxane, Aromadendrane and Pupukeanane Sesquiterpenoids Chemical investigation of the endophytic fungus Emericella sp. (HK-ZJ) isolated from the mangrove plant Aegiceras corniculatum led to the isolation of six farnesane sesquiterpenoids named emeriphenolicins A–F (338–343) (Figure9) with moderate anti-influenza A viral (H1N1) activities [ 80]. An unusual farnesane natural product (dotofide, 344) (Figure9), in which the terpenoid skeleton is interrupted by a guanidine moiety was obtained from the marine slug Doto pinnatifida [81]. Two spiroaxane sesquiterpenes, ( )-axisonitrile-3 (345), (+)-axamide-3 (346), and one aromadendrane − sesquiterpene axamide-2 (347) (Figure9) were isolated from the Thai marine sponge Halichondria sp., and only 345 showed strong activity to the HepG2 cell line withan IC50 value of 1.3 µM[69]. Fasciospyrinadine (348) (Figure9), a novel farnesane sesquiterpene pyridine alkaloid was extracted froma Guangxi sponge Fasciospongia sp. [82]. Molecules 2020, 25, x FOR PEER REVIEW 5 of 31

H H N O O O H NH O O NH N 330 2 N O O 2 H O OR 325 326 O 1 O R1 O O OH R2 H O R O OH H O 2 HN H O OH OH O N O 327 R =OH; R =H 331 R =MBT; R =H O N HO 1 2 1 2 HO O 328 R1=H; R2=H 332 R1=Tig; R2=H O 333 R =Tig; R =CH 329 R1=R2=O 1 2 3 334 335 O O O MBT= OH O OH O H O HO H O OH OH N Tig= O O N HO HO O O O 337 336 FigureFigure 8. The8. The structures structures ofof compoundscompounds 325325-337.–337 .

Apupukeanane-typeApupukeanane-type sesquiterpenoid sesquiterpenoid isomers,isomers, 9-thiocyanatopupukeanane isomers isomers (349 (–349350)– 350) (Figure(Figure9) were 9) isolated were fromisolated the from the Thai the sponge the ThaiHalichondria sponge Halichondriasp. [65]. Asp bioassay-guided [65]. A bioassay-guided phytochemical studyphytochemical was conducted study on was the semi-mangroveconducted on the plant semi-mangroveMyoporum plant bontioides Myoporum. A. Gray,bontioides which. A. ledGray, to the which led to the isolation of two new farnesane sesquiterpene alkaloids, myoporumines A (351) and isolation of two new farnesane sesquiterpene alkaloids, myoporumines A (351) and B (352) (Figure9), B (352) (Figure 9), which displayed potent anti-MRSA activity with MIC value of 6.25 μg/mL [83]. which displayed potent anti-MRSA activity with MIC value of 6.25 µg/mL [83]. Two aromadendrane Two aromadendrane sesquiterpene 1-isothiocyanatoaromadendrane (353) and 347, one spioaxane- sesquiterpenetype sesquiterpenoid 1-isothiocyanatoaromadendrane axamide-3 (354), and two (353 pupukeanane-type) and 347, one spioaxane-type sesquiterpenoids sesquiterpenoid (349, 350) axamide-3(Figure (354 9),), were and isolated two pupukeanane-type from the nudibranchs sesquiterpenoids Phyllidiellapustulosa (349 ,and350 Phyllidiacoelestis) (Figure9), were [67]. isolated from the nudibranchs Phyllidiella pustulosa and Phyllidia coelestis [67].

Figure 9. The structures of compounds 338–354.

2.8. Tremulane, Daucane, Brasilane, Salvialane, Aristolane, Bergamotane and Valerane Sesquiterpenoids

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Apupukeanane-type sesquiterpenoid isomers, 9-thiocyanatopupukeanane isomers (349–350) (Figure 9) were isolated from the the Thai sponge Halichondriasp [65]. A bioassay-guided phytochemical study was conducted on the semi-mangrove plant Myoporum bontioides. A. Gray, which led to the isolation of two new farnesane sesquiterpene alkaloids, myoporumines A (351) and B (352) (Figure 9), which displayed potent anti-MRSA activity with MIC value of 6.25 μg/mL [83]. Two aromadendrane sesquiterpene 1-isothiocyanatoaromadendrane (353) and 347, one spioaxane- Moleculestype2020 sesquiterpenoid, 25, 2485 axamide-3 (354), and two pupukeanane-type sesquiterpenoids (349, 35021) of 32 (Figure 9), were isolated from the nudibranchs Phyllidiellapustulosa and Phyllidiacoelestis [67].

FigureFigure 9. 9.The The structures structures of compounds compounds 338338–354.–354 .

2.8. Tremulane,2.8. Tremulane, Daucane, Daucane, Brasilane, Brasilane Salvialane,, Salvialane, Aristolane, Aristolane, Bergamotane Bergamotane and and Valerane Valerane Sesquiterpenoids Sesquiterpenoids

Huptremules A–D (compounds 355–358) (Figure 10) featuring unusual sesquiterpenoid-alkaloid hybrid structures that integrate the characteristics offungal metabolites (tremulane sesquiterpenoids) and the exogenous substrate, were isolated from a fungal endophyte of Huperzia serrata [84]. Compound 355–358 selectively inhibited acetylcholinesterase activities, with IC50 values of 0.99, 2.17, 0.11 and 0.06 µM, respectively [84]. Two daucane-type sesquiterpenoids, aculeneA (359) and B (360) (Figure 10), were identified from Aspergillus aculeatus, which were tested for antifungal activity against Candida albicans. However, all showed only weak orno activity [85]. One brasilane-type sesquiterpenoid, named diaporol L (361) (Figure 10) was isolated from Diaporthe sp., an endophytic fungus associated with the leaves of Rhizophora stylosa collected in Hainan Province, China [86]. One salvialane-type sesquiterpene halichon E (362) and one aristolane sesquiterpene epipolasin A (363) (Figure 10) were obtained from the Thai sponge Halichondria sp. [65]. Sporulaminals A (364) and B (365) (Figure 10), a pair of unusual epimericspiroaminal derivatives, bearing 6/4/5/5 tetracyclic ring system derived from bergamotane sesquiterpenoid, were isolated from a marine-derived fungus Paraconiothyrium sporulosum YK-03 [87]. Volvalerine A (366) (Figure 10), a novel N-containing valerane bisesquiterpenoid derivative with a dihydroisoxazole ring, was isolated from the roots of Valeriana officinalis var. latifolia [88]. Compound 366 was also evaluated for their enhancing activity on NGF mediated neurite outgrowth in PC12 cells. The result indicatedthat the proportion of the NGF-induced neurite-bearing cells (with NGF 5 ng/mL) was not enhanced by compound 366 at 50 µM[88]. Molecules 2020, 25, x FOR PEER REVIEW 6 of 31

Huptremules A–D (compounds 355–358) (Figure 10) featuring unusual sesquiterpenoid- alkaloid hybrid structures that integrate the characteristics offungal metabolites (tremulane sesquiterpenoids) and the exogenous substrate, were isolated from a fungal endophyte of Huperzia serrata [84]. Compound 355–358 selectively inhibited acetylcholinesterase activities, with IC50 values of 0.99, 2.17, 0.11 and 0.06 μM, respectively [84]. Two daucane-type sesquiterpenoids, aculeneA (359) and B (360) (Figure 10), were identified from Aspergillus aculeatus, which were tested for antifungal activity against Candida albicans. However, all showed only weak orno activity [85]. One brasilane- type sesquiterpenoid, named diaporol L (361) (Figure 10) was isolated from Diaporthe sp., an endophytic fungus associated with the leaves of Rhizophorastylosa collected in Hainan Province, China [86]. One salvialane-type sesquiterpene halichon E (362) and one aristolane sesquiterpene epipolasin A (363) (Figure 10) were obtained from the Thai sponge Halichondriasp [65]. Sporulaminals A (364) and B (365) (Figure 10), a pair of unusual epimericspiroaminal derivatives, bearing 6/4/5/5 tetracyclic ring system derived from bergamotane sesquiterpenoid, were isolated from a marine- derived fungus Paraconiothyrium sporulosum YK-03 [87]. Volvalerine A (366) (Figure 10), a novel N-containing valerane bisesquiterpenoid derivative with a dihydroisoxazole ring, was isolated from the roots of Valeriana officinalis var. latifolia [88]. Compound 366 was also evaluated for their enhancing activity on NGF mediated neurite outgrowth in PC12 cells. The result indicatedthat the proportion Moleculesof the2020 NGF-induced, 25, 2485 neurite-bearing cells (with NGF 5 ng/mL) was not enhanced by compound 36622 of 32 at 50 μM [88].

FigureFigure 10. 10.The The structures structures of compounds compounds 355355–366.–366 .

2.9. Cyclonerane,2.9. Cyclonerane, Axane, Axane, Nardosinane, Nardosinane, Zizaane, Zizaane, Eremophilane,Eremophilane, and and Guaiane Guaiane Sesquiterpenoids Sesquiterpenoids TheThe nitrogenous nitrogenous cycloneranesesquiterpenescyclonerincycloneranesesquiterpenescyclonerin A (367 A) and (367 B ()368 and) along B with (368 seven) along new with sevencongeners new congeners—deoxycyclonerins―deoxycyclonerins A–D (369–372 A–D), cyclonerinal( (369–372),373 cyclonerinal), and cyclonerizole (373), and (374 cyclonerizole) (Figure (374)11) (Figure―were 11 isolated)—were from isolated the culture from theof a culturemarine ofalgicolous a marine strain(A-YMD-9-2) algicolous strain(A-YMD-9-2) of Trichoderma of asperellum [89]. And, compounds (367–374) showed significant cytotoxic activityagainst harmful Trichoderma asperellum [89]. And, compounds (367–374) showed signiﬁcant cytotoxic activityagainst microalgae Chattonella marina with the IC50 value of 2.1–30 μg/mL [89]. Antartin (375) (Figure 11), a harmful microalgae Chattonella marina with the IC value of 2.1–30 µg/mL [89]. Antartin (375) cytotoxic zizaane-type sesquiterpenoid was obtained from50 a Streptomyces sp. SCO736, isolated from (Figurean Antarcticmarine11), a cytotoxic sediment, zizaane-type and showed sesquiterpenoid cytotoxicity wasagainst obtained A549, H1299, from aandStreptomyces U87 cancer cellsp. lines SCO736, isolatedby causing from an cell Antarctic cycle arrest marine at the sediment, G1 phase and[90]. showedOne eremophilane cytotoxicity sesquiterpene against A549, dendryphiellin H1299, and J U87 cancer(376 cell) (Figure lines by11) causingwas isolated cell from cycle the arrest marine-derived at the G1 phase fungus [ 90Cochlioboluslunatus]. One eremophilane SCSIO41401 sesquiterpene [91]. dendryphiellin J (376) (Figure 11) was isolated from the marine-derived fungus Cochliobolus lunatus

SCSIO41401 [91]. Compound 376, a rare naturally occurring aldoxime analogue, displayed cytotoxicities against ACHN and HepG-2 cells with IC50 values of 3.1 and 5.9 µM, respectively [91]. One unusual sesquiterpenoid dimer, nardochinoid B (377) (Figure 11) was isolated from Nardostachys chinensis Batal [92]. Compound 377 is the ﬁrst nitrogen-containing nornardosinane-aristolane sesquiterpene conjugate. The ED50 of compound 377 on the production of NO was 5.73, and obviously inhibited LPS-inducediNOS and COX-2 protein expression in a dose-dependent way, and increased HO-1 protein expression at the concentration of 10 µM[92].Three axane sesquiterpenoid isonitrile pictaisonitrile-1 (378), pictaisonitrile-2 (379), and cavernothiocyanate (380) (Figure 11) were extracted from hyllidiapicta collected from Bali, Indonesia [71]. Vlasoulamine A (381) (Figure 11), an unprecedented guaiane sesquiterpene lactone dimerfeaturing a fully hydrogenated pyrrolo[2,1,5-cd] indolizine core, was isolated from the roots of Vladimiria souliei [93]. Moreover, 381 exhibited neuroprotective activity whenevaluated for glutamate-induced cytotoxicity, nuclear Hoechst 33,258 staining, and measuring intracellular reactive oxygen species levels, using a rat pheochromocytoma PC12 cell-based model system [93]. Clavukoellians A–D (382–385) (Figure 11), highly rearranged nardosinane Sesquiterpenoids with antiangiogenic activity were puriﬁed from the marine soft coral Clavularia koellikeri [94]. Compound 382 has aunique skeleton with both lactone and maleimide ring systems, which is rare in natural products, and appears to be formed byoxidative cleavage of the C-7/C-8 bond of a nardosinane precursor with inhibiting the migration of the human umbilical veinendothelial cells (HUVECs) at 2.5 µM[94]. Molecules 2020, 25, x FOR PEER REVIEW 7 of 31

Compound 376, a rare naturally occurring aldoxime analogue, displayed cytotoxicities against ACHN and HepG-2 cells with IC50 values of 3.1 and 5.9 μM, respectively [91]. One unusual sesquiterpenoid dimer, nardochinoid B (377) (Figure 11) was isolated from Nardostachyschinensis Batal [92]. Compound 377 is the first nitrogen-containing nornardosinane-aristolane sesquiterpene conjugate. The ED50 of compound 377on the production of NO was 5.73, and obviously inhibited LPS- inducediNOS and COX-2 protein expression in a dose-dependent way,and increased HO-1 protein expression at the concentration of10 μM [92].Three axane sesquiterpenoid isonitrile pictaisonitrile-1 (378), pictaisonitrile-2 (379), and cavernothiocyanate (380) (Figure 11) were extracted from hyllidiapicta collected from Bali, Indonesia [71]. Vlasoulamine A (381) (Figure 11), an unprecedented guaiane sesquiterpene lactone dimerfeaturing a fully hydrogenated pyrrolo[2,1,5-cd] indolizine core, was isolated from the roots of Vladimiriasouliei [93]. Moreover, 381 exhibited neuroprotective activity whenevaluated for glutamate-induced cytotoxicity, nuclear Hoechst 33,258 staining, and measuring intracellular reactive oxygen species levels, using a rat pheochromocytoma PC12 cell-based model system [93]. Clavukoellians A–D (382-385) (Figure 11), highly rearranged nardosinane Sesquiterpenoids with antiangiogenic activity were purified from the marine soft coral Clavulariakoellikeri [94]. Compound 382 has aunique skeleton with both lactone and maleimide ring systems, which is rare in natural products, and appears to be formed byoxidative cleavage of the C- Molecules7/C-82020 bond, 25, 2485 of a nardosinane precursor with inhibiting the migration of the human umbilical23 of 32 veinendothelial cells (HUVECs) at 2.5 μM [94].

FigureFigure 11. 11.The The structuresstructures of of compounds compounds 367367–385.–385 .

2.10.2.10. Others Others FiveFive sesquiterpene sesquiterpene isocyanides, isocyanides, isothiocyanates, isothiocyanates, thiocyanates, thiocyanates, andformamides—halichon andformamides―halichon AA (386), halichon(386), Bhalichon (387), B halichon(387), halichon F ( 388F (388),), halichon halichon H H (389 (389), and), and(+)-2-thiocyanatoneopupukeanane (+)-2-thiocyanatoneopupukeanane (390) (390)(Figure (Figure 12) 12 ―)—were were isolated isolated from fromthe Thai the sponge Thai Halichondria sponge Halichondriasp [65]. Lamellodysidinesp. [65]. Lamellodysidine B (391) (Figure B 12), a sesquiterpenes isolated from the marine sponge Lamellodysideaherbacea, collected inIndonesia (391) (Figure 12), a sesquiterpenes isolated from the marine sponge Lamellodysidea herbacea, [95]. Biological activities of 391 was tested in our in-house screening including cytotoxicity, collectedMolecules inIndonesia 2020, 25, x FOR [95 PEER]. Biological REVIEW activities of 391 was tested in our in-house screening8 including of 31 cytotoxicity, antimicrobial activities, inhibitory activity of the cholesterol ester accumulation in macrophages,antimicrobial inhibitory activities, activityinhibitory of activity the RANKL-induced of the cholesterol formationester accumu oflation multinuclear in macrophages, osteoclasts, and inhibitory activity activities of the of theRANKL-induced ubiquitin-proteasome formation systemof multinuclear (proteasome, osteoclasts, E1,Ubc13 and inhibitory (E2) Uev1A activities of the ubiquitin-proteasome system (proteasome, E1,Ubc13 (E2)−Uev1A interaction, p53-− interaction, p53-Mdm2 (E3) interaction, and USP7). However, no signiﬁcant activity was detected Mdm2 (E3) interaction,and USP7). However, no significant activity was detected forthe compound forthe[95]. compound [95].

FigureFigure 12. 12.The The structuresstructures of of compounds compounds 386386–391.–391 .

3. Occurrence3. Occurrence NaturalNatural nitrogenous nitrogenous sesquiterpenoids sesquiterpenoids are are mainly mainly distributed distributed in species in species of plants of plantsbelonging belonging to to thethe Celastraceae,Celastraceae, Saxifragaceae,Saxifragaceae, Zingiberaceae, Zingiberaceae, Asteraceae, Asteraceae, Burseraceae, Burseraceae, Phyllanthaceae, Phyllanthaceae, Magnoliaceae,Magnoliaceae, Lamiaceae, Lamiaceae, Myoporaceae, Myoporaceae, and and Valerianaceae Valerianaceae families, families, marine marine sponges sponges belonging belonging to the Dysiseidae, Thorectidae, Spongiidae, and Halichodriae families, soft corals belonging to the to the Dysiseidae, Thorectidae, Spongiidae, and Halichodriae families, soft corals belonging to the Xeniidae and Clavulariidae families, phyllidid nudibranchs belonging to the Phyllidiidae family, marine slugs belonging to the Dotidae family), fungi belonging to the Trichocomaceae, Eurotiaceae, Parmulariaceae, Phanerochaetaceae, Diaporthaceae, and Pezizaceae families, bacteria belonging to the Pseudomonadaceae family, and actinomyces belonging to the Streptomycetaceae family (Table 3). Dihydroagarofuran sesquiterpenoids have been isolated from the roots of Maytenusmekongensis, the stems of M. oblongata, the leaves of M. spinosa, the roots and leaves of Tripterygium wilfordii, the stems of T.regelii, the root barks of T.hypoglaucum, the fruits of Celastrusorbiculatus, the seeds of C.paniculatus, the root barks of C.angulatus, the stems of Euonymus alatus, the whole plants of Parnassiawightiana, the leaves of Monimopetalumchinense. Friedo-drimane and drimane sesquiterpenes have been extracted from maring sponges of the following species: Dysidea sp., D. avara, D. fragilis, D. cinerea, D. septosa, Dactylospongia sp., D. elegans, and D. metachromia. Drimane sesquiterpenoids have been purified from the fungi Aspergillusochraceus, A. aculeatus, Talaromyces minioluteus, and Penicillium sp. ZZ1283, the bacteriumSaccharomonospora sp. CNQ-490, and the actinomycete Streptomycessp.Eudesmanesesquiterpenoids have been identified inmarine sponges of Halichondria sp., H. okadai, Axinyssasp., and A. variabilis, the soft coral Cespitulariataeniata, phyllidid nudibranchs of the Phyllidiella sp., P. pustulosa, and P. ocellatespeciesandthe plants Curcumaphaeocaulis and Inula helenium L.Germacranese squiterpenoids were isolated from the plants Onopordumalexandrinum, Magnolia kobus, and Salvia scapiformis. Cadinane sesquiterpenes were extracted from the plant Resinacommiphora, marine sponges like Halichondria sp. and Axinyssasp., phyllidid nudibranchs of the Phyllidiellasp. Bisabolane sesquiterpenoids have been isolated from Phyllanthus acidus (L.) skeels, Halichondria sp. Phyllidiella sp., Paraconiothyniumbrasiliense and P. sporulosum.

Table 3.The species containing nitrogenous sesquiterpenoids.

Classif Family Species Type Reference ication Maytenusmekongensis; [17,25,30] M. spinosa; M. oblongata Celastra Plant Tripterygium wilfordii; Dihydroagarofuran ceae [18,20,21,23,24,26,28, T. regelii; T. 29,31–33,36] hypoglaucum

Molecules 2020, 25, 2485 24 of 32

Xeniidae and Clavulariidae families, phyllidid nudibranchs belonging to the Phyllidiidae family, marine slugs belonging to the Dotidae family), fungi belonging to the Trichocomaceae, Eurotiaceae, Parmulariaceae, Phanerochaetaceae, Diaporthaceae, and Pezizaceae families, bacteria belonging to the Pseudomonadaceae family, and actinomyces belonging to the Streptomycetaceae family (Table3). Dihydroagarofuran sesquiterpenoids have been isolated from the roots of Maytenus mekongensis, the stems of M. oblongata, the leaves of M. spinosa, the roots and leaves of Tripterygium wilfordii, the stems of T. regelii, the root barks of T. hypoglaucum, the fruits of Celastrus orbiculatus, the seeds of C. paniculatus, the root barks of C. angulatus, the stems of Euonymus alatus, the whole plants of Parnassia wightiana, the leaves of Monimopetalum chinense. Friedo-drimane and drimane sesquiterpenes have been extracted from maring sponges of the following species: Dysidea sp., D. avara, D. fragilis, D. cinerea, D. septosa, Dactylospongia sp., D. elegans, and D. metachromia. Drimane sesquiterpenoids have been puriﬁed from the fungi Aspergillus ochraceus, A. aculeatus, Talaromyces minioluteus, and Penicillium sp. ZZ1283, the bacterium Saccharomonospora sp. CNQ-490, and the actinomycete Streptomyces sp. Eudesmane sesquiterpenoids have been identiﬁed inmarine sponges of Halichondria sp., H. okadai, Axinyssa sp., and A. variabilis, the soft coral Cespitularia taeniata, phyllidid nudibranchs of the Phyllidiella sp., P. pustulosa, and P. ocellate species and the plants Curcuma phaeocaulis and Inula helenium L. Germacranese squiterpenoids were isolated from the plants Onopordum alexandrinum, Magnolia kobus, and Salvia scapiformis. Cadinane sesquiterpenes were extracted from the plant Resina commiphora, marine sponges like Halichondria sp. and Axinyssa sp., phyllidid nudibranchs of the Phyllidiella sp. Bisabolane sesquiterpenoids have been isolated from Phyllanthus acidus (L.) skeels, Halichondria sp. Phyllidiella sp., Paraconiothynium brasiliense and P. sporulosum.

Table 3. The species containing nitrogenous sesquiterpenoids.

Classiﬁcation Family Species Type Reference Maytenus mekongensis; M. [17,25,30] spinosa; M. oblongata Celastraceae Tripterygium wilfordii; Dihydroagarofuran [18,20,21,23,24,26, T. regelii; T. 28,29,31–33,36] hypoglaucum Celastrus orbiculatus; C. angulatus; C. [19,34,37] paniculatus Euonymus alatus [22] Monimopetalum [35] Plant chinense Saxifragaceae Parnassia wightiana [27] Zingiberaceae Curcuma phaeocaulis Eudesmane; Elemene [63] Inula helenium L. Eudesmane [68] Asteraceae Onopordum Germacrane; Elemene [79] alexandrinum Vladimiria souliei Guaiane [93] Burseraceae Resina commiphora Cadinane [72] Phyllanthus acidus (L.) Phyllanthaceae Bisabolane [75] skeels Magnoliaceae Magnolia kobus Germacrane [76] Lamiaceae Salvia scapiformis Germacrane [78] Myoporaceae Myoporum bontioides Farnesane [83] Valeriana oﬃcinalis Valerane [88] Valerianaceae var. latifolia Nardostachys chinensis Nornardosinane-aristolane [92] Molecules 2020, 25, 2485 25 of 32

Table 3. Cont.

Classiﬁcation Family Species Type Reference Dysidea sp.; D. avara; Dysiseidae D. fragilis; D. cinerea; [43,45,48,53,55,56] D. septosa Dactylospongia sp.; D. friedo-drimane elegans; D. [44,47,51,52,54] Thorectidae metachromia Smenospongia aurea, S. cerebriformis, and [49] Sponge Verongula rigida Verongula cf. rigida [57] Esper Hippospongia sp. [46] Spongiidae Spongiapertusa Esper [50] Eudesmane; Cadinane; Spiroaxane; Aromadendrane; Halichondria sp.; H. Bisabolane; [60–62,65,69,74,77] Halichodriae okadai Pupukeanane; Salvialane; Aristolane; Iresane Axinyssa sp.; A. Eudesmane; Cadinane; [66,70] variabilis Bisabolene Thorectidae Fasciospongia sp. Farnesane [82] Xeniidae Cespitularia taeniata Eudesmane [64] Soft coral Clavulariidae Clavularia koellikeri Nardosinane [94] Eudesmane; Cadinane; Bisabolane; Farnesane, Phyllidid Phyllidiella sp.; P. Phyllidiidae spiroaxane; [67,71] nudibranchs pustulosa; P. ocellata aromadendrane; pupukeanane; Axane Marine slug Dotidae Doto pinnatiﬁda Farnesane [81] Aspergillus ochraceus; Drimane; Daucane [38,39,85] A. aculeatus Trichocomaceae Talaromyces Drimane [40] minioluteus Emericella sp. Farnesane [80] Penicillium sp. Eurotiaceae Drimane [41] Fungus ZZ1283. Paraconiothynium Bisabolane; Parmulariaceae brasiliense; P. [73,87] Bergamotane sporulosum Phanerochaetaceae Ceriporia lacerate Tremulane [84] Diaporthaceae Diaporthe sp. Brasilane [86] Trichoderma Moniliaceae Cyclonerane [89] asperellum Pezizaceae Cochliobolus lunatus Eremophilane [91] Saccharomonospora sp. Bacteria Pseudomonadaceae Drimane [42] CNQ-490 Actinomyces Streptomycetaceae Streptomyces sp. Drimane; Zizaane [58,59,90]

4. Conclusions In summary, a total of 391 bioactive nitrogenous sesquiterpenoids have been isolated and characterized from plants, microorganisms, and marine organisms at the past ten years. This report systematically describes the occurrence, isolation, structures and biological activities ofthese nearly 400 natural products that contain a nitrogen-carbon/nitrogen-nitrogen/nitrogen-sulfurbond. These natural products are dispersed over severalstructural classes, isolated from many different Molecules 2020, 25, 2485 26 of 32 sources (bothmarine and terrestrial) and possess a diverse array of biological activities. It can be concluded that the structure types are obviously related to the species sources, and the bioactivities of nitrogenous sesquiterpenoids are obviously related to structure types, being particularly important their cytotoxic activities. The important points arising from this review are the following: (1) There are few structural types of N-containing sesquiterpenes in plants, while the structural types of sesquiterpenes with nitrogen in marine resources and microorganisms are various and diverse. (2) Dihydroagarofuran sesquiterpenoids were considered the most widespread and characteristic metabolites of the plants of Celastraceae, which are well recognized as characteristic metabolitesand important chemotaxonomic markers or indicators of the family, exceptforsome β-dihydroagarofurans obtained from the Saxifragaceae species Parnassia wightiana. (3) Sponges and their associated microorganisms are the largest contributors of nitrogenous sesquiterpenoids. Rearranged 4,9-friedo-drimaneterpenoid skeletons represent the majority ofnitrogen-contenting sesquiterpenes isolated from marine sponges. The types of sesquiterpenoids that are the most abundant among the marine organisms, Halichondria sp. (sponge) and Phyllidiella sp. (nudibranchs), are all sesquiterpene isocyanides, isothiocyanates, thiocyanates, and formamides. (4) Nitrogenous sesquiterpenes are rich in microorganisms, such as fungus, bacteria and actinomyces and the main skeleton types are drimane, bisabolane, farnesane, tremulane sesquiterpenoids and so on. (5) Dihydroagarofuran sesquiterpenoids show significant anti-inflammatory, neuroprotective, and immunosuppressive effects, while sesquiterpenes isolated from marine organisms exhibit remarkable antitumor cytotoxic activities. Due to the rich activities and structural diversity of N-contenting sesquiterpenes, researchers have not stopped exploring and studying such compounds. We hope this review will stimulate further researchinto this interesting class of nitrogenous secondary metabolites.

Funding: ThisMolecules work was 2020 supported, 25, x FOR PEER in part REVIEW by Hainan Provincial Natural Science Foundation of China 11 of 31 (No. 219MS101), the National Natural Science Foundation of China (No. 81603387), the CAMS Innovation Fund for Medical Sciences (CIFMS) (Nos. 2016-I2M-1-012and 2017-I2M-1-013), the General Programof the Natural Molecules 2020, 25, x FOR PEER REVIEW 11 of 31 Science FoundationFoundation of Beijing, of Beijing, China (No. China 7082059), (No. 7082059), and Basic and research Basic resear projectsch projects of central-level of central-level public welfarepublic welfare research research institutesinstitutes (No. 2018PT35030). (No. 2018PT35030). FoundationMolecules 2020 of, 25Beijing,, x FOR ChinaPEER REVIEW (No. 7082059), and Basic research projects of central-level public welfare research11 of 31 Conﬂicts of Interest:institutesConflictsThe (No. of authors Interest:2018PT35030). declare The noauthors conﬂict declare of interest. no conflict of interest. MoleculesFoundation 2020 ,of 25 Beijing,, x FOR PEER China REVIEW (No. 7082059), and Basic research projects of central-level public welfare research11 of 31 AbbreviationsConflictsinstitutesAbbreviations of(No. Interest: 2018PT35030). The authors declare no conflict of interest. Foundation of Beijing, China (No. 7082059), and Basic research projects of central-level public welfare research Conflicts of Interest: The authors declare no conflict of interest. Abbreviationsinstitutes (No. 2018PT35030).

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References1. Zhan, Z.J.; Ying, Y.M.; Ma, L.F.; Shan, W.G. Natural disesquiterpenoids. Nat. Prod. Rep. 2011, 28, 594–629. 2. Hanson, J. A hundred years in the elucidation of the structures of natural products. Sci. Progress 2017, 100,

1.References Zhan,63–79. Z.J.; Ying, Y.M.; Ma, L.F.; Shan, W.G. Natural disesquiterpenoids. Nat. Prod. Rep. 2011, 28, 594–629. 2. Hanson, J. A hundred years in the elucidation of the structures of natural products. Sci. Progress 2017, 100, References1.3. Zhan,Bishayee, Z.J.; Ying,A.; Sethi, Y.M.; G. Ma, Bioactive L.F.; Shan, natural W.G. products Natural in disesquiterpenoids. cancer prevention and Nat. therapy: Prod. Rep. Progress 2011, 28 and, 594–629. promise. 63–79. 2. Hanson,Semin CancerBiol J. A hundred. 2016 years, 40, 1–3.in the elucidation of the structures of natural products. Sci. Progress 2017, 100, 3.1. Bishayee,Zhan, Z.J.; A.; Ying, Sethi, Y.M.; G. BioactiveMa, L.F.; naShan,tural W.G. products Natural in cancerdisesquiterpenoids. prevention and Nat. therapy: Prod. Rep. Progress 2011, and28, 594–629. promise. 4. 63–79.Newman, D.J.; Cragg, G.M. Natural Products as Sources of new drugs over the nearly four decades from 2. SeminHanson, CancerBiol J. A hundred. 2016 ,years 40, 1–3. in the elucidation of the structures of natural products. Sci. Progress 2017, 100, 3. Bishayee,01/1981 to A.; 09/2019. Sethi, G. J. BioactiveNat. Prod. na2020tural, 83 products, 770–803. in cancer prevention and therapy: Progress and promise. 4. Newman,63–79. D.J.; Cragg, G.M. Natural Products as Sources of new drugs over the nearly four decades from 5. SeminNewman, CancerBiol D.J.; Cragg,. 2016, 40G.M., 1–3. Natural products as sources of new drugs over the 30 Years from 1981 to 2010. 3. 01/1981Bishayee, to A.;09/2019. Sethi, J.G. Nat. Bioactive Prod. 2020 natural, 83, products770–803. in cancer prevention and therapy: Progress and promise. 4. Newman,J. Nat. Prod D.J.;. 2012 Cragg,, 75, 311–335.G.M. Natural Products as Sources of new drugs over the nearly four decades from 5. Newman,Semin CancerBiol D.J.; Cragg,. 2016 ,G.M. 40, 1–3. Natural products as sources of new drugs over the 30 Years from 1981 to 2010. 6. 01/1981Paterson, to 09/2019.I.; Anderson, J. Nat. E.A. Prod The. 2020 renaissance, 83, 770–803. of natural products as drug candidates. Science 2005, 310, 451– 4. J.Newman, Nat. Prod D.J.;. 2012 Cragg,, 75, 311–335. G.M. Natural Products as Sources of new drugs over the nearly four decades from 5. Newman,453. D.J.; Cragg, G.M. Natural products as sources of new drugs over the 30 Years from 1981 to 2010. 6. Paterson,01/1981 to I.; 09/2019. Anderson, J. Nat. E.A. Prod The. 2020 renaissance, 83, 770–803. of natural products as drug candidates. Science 2005, 310, 451– 7. J.Vasas, Nat. Prod A.;. Hohmann,2012, 75, 311–335. J. Xanthanesesquiterpenoids: Structure, synthesis and biological activity. Nat. Prod. 5. 453.Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the 30 Years from 1981 to 2010. 6. Paterson,Rep. 2011 I.;, 28 Anderson,, 824–842. E.A. The renaissance of natural products as drug candidates. Science 2005, 310, 451– 7. Vasas,J. Nat. ProdA.; Hohmann,. 2012, 75, 311–335. J. Xanthanesesquiterpenoids: Structure, synthesis and biological activity. Nat. Prod. 453. 6. RepPaterson,. 2011, I.;28 Anderson,, 824–842. E.A. The renaissance of natural products as drug candidates. Science 2005, 310, 451– 7. Vasas, A.; Hohmann, J. Xanthanesesquiterpenoids: Structure, synthesis and biological activity. Nat. Prod. 453. Rep. 2011, 28, 824–842. 7. Vasas, A.; Hohmann, J. Xanthanesesquiterpenoids: Structure, synthesis and biological activity. Nat. Prod. Rep. 2011, 28, 824–842.

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FoundationMolecules 2020 of, 25 Beijing,, x FOR PEERChina REVIEW (No. 7082059), and Basic research projects of central-level public welfare research11 of 31 institutes (No. 2018PT35030). FoundationMolecules 2020 of, Beijing,25, x FOR China PEER (No.REVIEW 7082059), and Basic research projects of central-level public welfare research11 of 31 Conflictsinstitutes (No.of Interest: 2018PT35030). The authors declare no conflict of interest. MoleculesFoundation 2020 of, 25 Beijing,, x FOR PEERChina REVIEW (No. 7082059), and Basic research projects of central-level public welfare research11 of 31 Conflictsinstitutes of (No. Interest: 2018PT35030). The authors declare no conflict of interest. AbbreviationsFoundation of Beijing, China (No. 7082059), and Basic research projects of central-level public welfare research AbbreviationsinstitutesConflicts (No.of Interest: 2018PT35030). The authors declare no conflict of interest. ConflictsOAc of Interest: The authors declare no conflict of interest. Abbreviations OAc Abbreviations OAc OBz OAc OBz

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1.References Zhan, Z.J.; Ying, Y.M.; Ma, L.F.; Shan, W.G. Natural disesquiterpenoids. Nat. Prod. Rep. 2011, 28, 594–629. 2. Hanson, J. A hundred years in the elucidation of the structures of natural products. Sci. Progress 2017, 100, 1.References Zhan, Z.J.; Ying, Y.M.; Ma, L.F.; Shan, W.G. Natural disesquiterpenoids. Nat. Prod. Rep. 2011, 28, 594–629. 63–79. 2. Hanson, J. A hundred years in the elucidation of the structures of natural products. Sci. Progress 2017, 100, 3.References1. Bishayee,Zhan, Z.J.; A.; Ying, Sethi, Y.M.; G. Bioactive Ma, L.F.; na Shan,tural W.G.products Natural in cancer disesquiterpenoids. prevention and Nat. therapy: Prod. ProgressRep. 2011 and, 28, promise.594–629. References 63–79. 2. SeminHanson, CancerBiol J. A hundred. 2016, 40 years, 1–3. in the elucidation of the structures of natural products. Sci. Progress 2017, 100, 1. Zhan, Z.J.;3.1. Ying,Bishayee,Zhan, Y.M.; Z.J.; A.; Ma, Ying, Sethi, L.F.; Y.M.; G. Shan, Bioactive Ma, W.G. L.F.; Naturalna Shan,tural W.G. products disesquiterpenoids. Natural in cancer disesquiterpenoids. preventionNat. Prod. and Rep. Nat. therapy:2011 Prod., 28 ProgressRep., 594–629. 2011 ,and 28, promise.594–629. 4. Newman,63–79. D.J.; Cragg, G.M. Natural Products as Sources of new drugs over the nearly four decades from [CrossRef2. ][PubMedSeminHanson, CancerBiol] J. A hundred. 2016, 40years, 1–3. in the elucidation of the structures of natural products. Sci. Progress 2017, 100, 3. 01/1981Bishayee, to 09/2019. A.; Sethi, J. G.Nat. Bioactive Prod. 2020 natural, 83, 770–803. products in cancer prevention and therapy: Progress and promise. 2. Hanson,4. J. ANewman,63–79. hundred yearsD.J.; Cragg, in the elucidationG.M. Natural of Products the structures as Sources of natural of new products. drugs overSci. Progressthe nearly2017 four, 100 decades, from 5. Newman,Semin CancerBiol D.J.; Cragg,. 2016 G.M., 40, Natural1–3. products as sources of new drugs over the 30 Years from 1981 to 2010. 63–79. [CrossRef3. 01/1981Bishayee,][PubMed to 09/2019.A.; Sethi,] J. G. Nat. Bioactive Prod. 2020 natural, 83, 770–803.products in cancer prevention and therapy: Progress and promise. 4. J. Newman,Nat. Prod. D.J.;2012 ,Cragg, 75, 311–335. G.M. Natural Products as Sources of new drugs over the nearly four decades from 3. Bishayee,5. A.;Newman,Semin Sethi, CancerBiol G. BioactiveD.J.; Cragg,. 2016 natural G.M., 40, 1–3. productsNatural products in cancer as prevention sources of andnew therapy: drugs over Progress the 30 andYears promise. from 1981 to 2010. 6. Paterson,01/1981 toI.; 09/2019.Anderson, J. Nat. E.A. Prod The. renaissance2020, 83, 770–803. of natural products as drug candidates. Science 2005, 310, 451– Semin. Cancer4. J.Newman, Nat. Biol. Prod2016 ., D.J.;201240, 1–3.Cragg,, 75, [311–335.CrossRef G.M. Natural ] Products as Sources of new drugs over the nearly four decades from 5. 453.Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the 30 Years from 1981 to 2010. 4. Newman,6. D.J.;Paterson,01/1981 Cragg, to I.; G.M. 09/2019. Anderson, Natural J. Nat. E.A. Products Prod The. renaissance2020 as, Sources 83, 770–803. of of natural new drugs products over as the drug nearly candidates. four decades Science from 2005, 310, 451– 7. Vasas,J. Nat. A.; Prod Hohmann,. 2012, 75, J.311–335. Xanthanesesquiterpenoids: Structure, synthesis and biological activity. Nat. Prod. 01/19815. to 09453./Newman,2019. J. Nat. D.J.; Prod. Cragg,2020 G.M., 83, 770–803.Natural products [CrossRef as] sources of new drugs over the 30 Years from 1981 to 2010. 6. RepPaterson,. 2011, 28 I.;, Anderson,824–842. E.A. The renaissance of natural products as drug candidates. Science 2005, 310, 451– 5. Newman,7. D.J.;Vasas,J. Nat. Cragg, A.;Prod G.M.Hohmann,. 2012 Natural, 75, J.311–335. Xanthanesesquiterpenoids: products as sources of new drugsStructure, over synthesis the 30 Years and from biological 1981 to activity. 2010. Nat. Prod. 453. J. Nat. Prod.6. Rep2012Paterson,. ,201175, 311–335., 28I.;, Anderson,824–842. [CrossRef E.A.] The renaissance of natural products as drug candidates. Science 2005, 310, 451– 7. Vasas, A.; Hohmann, J. Xanthanesesquiterpenoids: Structure, synthesis and biological activity. Nat. Prod. 6. Paterson, I.; Anderson,453. E.A. The renaissance of natural products as drug candidates. Science 2005, 310, Rep. 2011, 28, 824–842. 451–453.7. [ CrossRefVasas,][ A.;PubMed Hohmann,] J. Xanthanesesquiterpenoids: Structure, synthesis and biological activity. Nat. Prod. 7. Vasas, A.; Hohmann,Rep. 2011 J., Xanthanesesquiterpenoids: 28, 824–842. Structure, synthesis and biological activity. Nat. Prod. Rep. 2011, 28, 824–842. [CrossRef] 8. Ghantous, A.; Gali-Muhtasib, H.; Vuorela, H.; Saliba, N.A.; Darwiche, N. What madesesquiterpene lactones reach cancer clinical trials? Drug Discov. Today 2010, 15, 668–678. [CrossRef] 9. Chadwick, M.; Trewin, H.; Gawthrop, F.; Wagstaff, C. Sesquiterpenoidslactones: Benefits to plants and people. Int. J. Mol. Sci. 2013, 14, 12780–12805. [CrossRef] 10. Alarif, W.M.; Abdel-Lateff, A.; Alorfi, H.S.; Alburae, N.A. Alcyonacea: A potential source for production of nitrogen-containing metabolites. Molecules 2019, 24, 286. [CrossRef] 11. Fraga, B.M. Natural sesquiterpenoids. Nat. Prod. Rep. 2012, 29, 1334–1376. [CrossRef][PubMed] 12. Fraga, B.M. Natural sesquiterpenoids. Nat. Prod. Rep. 2013, 30, 1226–1264. [CrossRef][PubMed] 13. Ma, L.F.; Chen, Y.L.; Shan, W.G.; Zhan, Z.J. Natural disesquiterpenoids: An update. Nat. Prod. Rep. 2020. [CrossRef][PubMed] 14. Liao, S.G.; Yue, J.M. Dimeric sesquiterpenoids. Prog. Chem. Org. Nat. Prod. 2016, 101, 1–112. 15. Blair, L.M.; Sperry, J. Natural products containing a nitrogen nitrogen bond. J. Nat. Prod. 2013, 76, 794–812. − [CrossRef][PubMed] Molecules 2020, 25, 2485 28 of 32

16. Petkowski, J.J.; Bains, W.; Seager, S. Natural products containing a nitrogen-sulfur bond. J. Nat. Prod. 2018, 81, 423–446. [CrossRef][PubMed] 17. Lhinhatrakool, T.; Prabpai, S.; Kongsaeree, P.; Sutthivaiyakit, S. Antiplasmodial sesquiterpene alkaloids from the roots of Maytenus mekongensis. J. Nat. Prod. 2011, 74, 1386–1391. [CrossRef] 18. Luo, Y.G.; Min, Z.; Qi, Y.; Qiang, P.; Zhang, G.L. Dihydroagarofuran derivatives from the dried roots of Tripterygium wilfordii. J. Nat. Prod. 2012, 75, 98–102. [CrossRef] 19. Xu, J.; Xie, C.F.; Jin, D.Q.; Guo, Y.Q.; Zhao, P.; Wang, S.N.; He, Y.S. Three new dihydroagarofuran sesquiterpenoids from Celastrus orbiculatus. Phytochem. Lett. 2012, 5, 713–716. [CrossRef] 20. Li, C.J.; Xie, F.G.; Yang, J.Z.; Luo, Y.M.; Chen, X.G.; Zhang, D.M. Two sesquiterpene pyridine alkaloids and a triterpenoid saponin from the root barks of Tripterygium hypoglaucum. J. Asian Nat. Prod. Res. 2012, 14, 973–980. [CrossRef] 21. Wang, C.; Li, C.J.; Yang, J.Z.; Ma, J.; Chen, X.G.; Hou, Q.; Zhang, D.M. Anti-inflammatory sesquiterpene derivatives from the Leaves of Tripterygium wilfordii. J. Nat. Prod. 2013, 76, 85–90. [CrossRef][PubMed] 22. Yan, Z.H.; Han, Z.Z.; Hu, X.Q.; Liu, Q.X.; Zhang, W.D.; Liu, R.H.; Li, H.L. Two new sesquiterpenes from Euonymus alatus. Helv. Chim Acta 2013, 96, 85–92. [CrossRef] 23. Wang, C.; Li, C.J.; Ma, J.; Yang, J.Z.; Chen, X.G.; Hou, Q.; Zhang, D.M. Bioactive sesquiterpene polyol esters from the leaves of Tripterygium wilfordii. Fitoterapia 2014, 96, 103–108. [CrossRef] 24. Luo, Y.G.; Pu, X.; Luo, G.Y.; Zhou, M.; Ye, Q.; Liu, Y.; Gu, J.; Qi, H.Y.; Li, G.Y.; Zhang, G.L. Nitrogen-containing dihydro-β-agarofuran derivatives from Tripterygium wilfordii. J. Nat. Prod. 2014, 77, 1650–1657. [CrossRef] [PubMed] 25. Fatima, G.N.; Juan, C.O.; Ángel, G.R.; Ana, E.B. β-Agarofurans and sesquiterpene pyridine alkaloids from Maytenus spinosa. J. Nat. Prod. 2014, 77, 1853–1863. 26. Gao, C.; Huang, X.X.; Bai, M.; Wu, J.; Li, J.Y.; Liu, Q.B.; Li, L.Z.; Song, S.J. Anti-inflammatory sesquiterpene pyridine alkaloids from Tripterygium wilfordii. Fitoterapia 2015, 105, 49–54. [CrossRef] 27. Gao, Z.F.; Zhou, B.H.; Zhao, J.Y.; Cao, F.J.; Zhou, L.; Geng, H.L. Further study on chemical constituents of Parnassia wightiana Wall: Four new dihydro-β-agarofuran sesquiterpene polyesters. Int. J. Mol. Sci. 2015, 16, 9119–9133. [CrossRef] 28. Fan, D.S.; Zhu, G.Y.; Chen, M.; Xie, L.M.; Jiang, Z.H.; Xu, L.; Bai, L.P. Dihydro-β-agarofuran sesquiterpene polyesters isolated from the stems of Tripterygium regelii. Fitoterapia 2016, 112, 1–8. [CrossRef] 29. Fan, D.S.; Zhu, G.Y.; Li, T.; Jiang, Z.H.; Bai, L.P. Dimacrolide sesquiterpene pyridine alkaloids from the stems of Tripterygium regelii. Molecules 2016, 21, 1146. [CrossRef] 30. Toure, S.; Nirma, C.; Falkowski, M.; Dusfour, I.; Boulogne, I.; Jahn-Oyac, A.; Coke, M.; Azam, D.; Girod, R.; Moriou, C.; et al. Aedes aegypti larvicidal sesquiterpene alkaloids from Maytenus oblongata. J. Nat. Prod. 2017, 80, 384–390. [CrossRef] 31. Gao, C.; Lou, L.L.; Wang, D.; Zhang, Y.; Huang, X.X.; Song, S.J. Chemical constituents from the roots of Tripterygium wilfordii and their cytotoxic activity. J. Asian Nat. Prod. Res. 2017, 19, 725–731. [CrossRef] [PubMed] 32. Chen, F.Y.; Li, C.J.; Ma, J.; Zhou, J.; Li, L.; Zhang, Z.; Chen, N.H.; Zhang, D.M. Neuroprotective dihydroagarofuran sesquiterpene derivatives from the leaves of Tripterygium wilfordii. J. Nat. Prod. 2018, 81, 270–278. [CrossRef][PubMed] 33. Chen, F.Y.; Luo, Y.M.; Li, C.J.; Ma, J.; Huang, J.W.; Li, C.; Zhang, D.M. Dihydroagarofuran sesquiterpenoids esterified with organic acids from the leaves of Tripterygium wilfordii. Fitoterapia 2019, 137, 104185. [CrossRef] [PubMed] 34. Chang, X.; Wang, Z.Y.; Chen, X.; Ma, Y.N.; Zhang, H.Y.; Zhao, T.Z. Two new sesquiterpene pyridine alkaloids from root barks of Celastrus angulatus. J. Asian Nat. Prod. Res. 2019, 21, 1043–1051. [CrossRef][PubMed] 35. Zhao, X.Z.; Yin, M.; Wang, X.Y.; Guo, S.H.; Li, D.L.; Feng, X.; Xu, S. Two new dihydro-β-agarofuran sesquiterpenes from stems and leaves of Monimopetalum chinense. Chin. Trad. Herbal Drugs 2019, 50, 13–16. 36. Zhao, P.; Lin, B.; Hou, Z.L.; Zhou, L.; He, Q.J.; Yao, G.D.; Huang, X.X.; Song, S.J. Dihydro-β-agarofuran sesquiterpenoid derivatives with neuroprotective activity from the leaves of Tripterygium wilfordii. Fitoterapia 2020, 142, 104501. [CrossRef] 37. Fu, Y.F.; Zhao, W.M. Polyesterified sesquiterpenoids from the seeds of Celastrus paniculatus as lifespan-extending agents for the nematode Caenorhabditis elegans. J. Nat. Prod. 2020, 83, 505–515. Molecules 2020, 25, 2485 29 of 32

38. Fang, W.; Lin, X.P.; Zhou, X.F.; Wan, J.T.; Lu, X.; Yang, B.; Ai, W.; Lin, J.; Zhang, T.Y.; Tu, Z.C.; et al. Cytotoxic and antiviral nitrobenzoyl sesquiterpenoids from the marine-derived fungus Aspergillus ochraceus Jcma1F17. Med. Chem. Commun. 2014, 5, 701–706. [CrossRef] 39. Tan, Y.H.; Yang, B.; Lin, X.P.; Luo, X.W.; Pang, X.Y.; Tang, L.; Liu, Y.H.; Li, X.J.; Zhou, X. F Nitrobenzoyl sesquiterpenoids with cytotoxic activities from a marine-derived Aspergillus ochraceus Fungus. J. Nat. Prod. 2018, 81, 92–97. [CrossRef] 40. Ngokpol, S.; Suwakulsiri, W.; Sureram, S.; Lirdprapamongkol, K.; Aree, T.; Wiyakrutta, S.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P. Drimane sesquiterpene-conjugated amino acids from a marine isolate of the fungus Talaromyces minioluteus (Penicillium minioluteum). Mar. Drugs 2015, 13, 3567–3580. [CrossRef] 41. Kaleem, S.; Ge, H.J.; Yi, W.W.; Zhang, Z.Z.; Wu, B. Isolation, structural elucidation, and antimicrobial evaluation of the metabolites from a marine-derived fungus Penicillium sp. ZZ1283. Nat. Prod. Res. 2019, 1680669. [CrossRef][PubMed] 42. Le, T.C.; Lee, E.J.; Lee, J.; Hong, A.; Yim, C.Y.; Yang, I.; Choi, H.; Chin, J.; Cho, S.J.; Ko, J.; et al. Saccharoquinoline, a cytotoxic alkaloidal meroterpenoid from marine-derived bacterium Saccharomonospora sp. Mar. Drugs 2019, 17, 98. [CrossRef][PubMed] 43. Utkina, N.K.; Denisenko, V.A.; Krasokhin, V.B. Sesquiterpenoid aminoquinones from the marine sponge Dysidea sp. J. Nat. Prod. 2010, 73, 788–791. [CrossRef][PubMed] 44. Ovenden, S.P.B.; Nielson, J.L.; Liptrot, C.H.; Willis, R.H.; Tapiolas, D.M.; Wright, A.D.; Motti, C.A. Sesquiterpene benzoxazoles and sesquiterpene quinones from the marine sponge Dactylospongia elegans. J. Nat. Prod. 2011, 74, 65–68. [CrossRef] 45. Hamed, A.N.E.; Wätjen, W.; Schmitz, R.; Chovolou, Y.; Edrada-Ebel, R.A.; Youssef, D.T.A.; Kamel, M.S.; Proksch, P.A new bioactive sesquiterpenoid quinone from the Mediterranean Sea marine sponge Dysideaavara. Nat. Prod. Commun. 2013, 8, 89–92. 46. Kumar, R.; Subramani, R.; Aalbersberg, W. Three bioactive sesquiterpene quinones from the Fijian marine sponge of the genus Hippospongia. Nat. Prod. Res. 2013, 27, 1488–1491. [CrossRef] 47. Daletos, G.; Voogd, N.J.; Müller, W.E.G.; Wray, V.; Lin, W.H.; Feger, D.; Kubbutat, M.; Aly, A.H.; Proksch, P. Cytotoxic and protein kinase inhibiting nakijiquinones and nakijiquinols from the sponge Dactylospongia metachromia. J. Nat. Prod. 2014, 77, 218–226. [CrossRef] 48. Jiao, W.H.; Xu, T.T.; Yu, H.B.; Mu, F.R.; Li, J.; Li, Y.S.; Yang, F.; Han, B.N.; Lin, H.W. Dysidaminones A-M, cytotoxic and NF-kB inhibitory sesquiterpene aminoquinones from the South China Sea sponge Dysidea fragilis. RSC Adv. 2014, 4, 9236–9246. [CrossRef] 49. Hwang, I.H.; Oh, J.; Zhou, W.; Park, S.; Kim, J.H.; Chittiboyina, A.G.; Ferreira, D.; Song, G.Y.; Oh, S.; Na, M.K.; et al. Cytotoxic activity of rearranged drimane meroterpenoids against colon cancer cells via down-regulation of β-catenin expression. J. Nat. Prod. 2015, 78, 453–461. [CrossRef] 50. Li, J.; Gu, B.B.; Sun, F.; Xu, J.R.; Jiao, W.H.; Yu, H.B.; Han, B.N.; Yang, F.; Zhang, X.C.; Lin, H.W. Sesquiterpene quinones/hydroquinones from the marine sponge Spongiapertusa Esper. J. Nat. Prod. 2017, 80, 1436–1445. [CrossRef] 51. Li, J.; Yang, F.; Wang, Z.; Wu, W.; Liu, L.; Wang, S.P.; Zhao, B.X.; Jiao, W.H.; Xu, S.H.; Lin, H.W. Unusual anti-inﬂammatory meroterpenoids from the marine sponge Dactylospongia sp. Org. Biomol. Chem. 2018, 16, 6773–6783. [CrossRef][PubMed] 52. Balansa, W.; Mettal, U.; Wuisan, Z.G.; Plubrukarn, A.; Ijong, F.G.; Liu, Y.; Schäberle, T.F. A new sesquiterpenoid aminoquinone from an Indonesian marine sponge. Mar. Drugs 2019, 17, 158. [CrossRef][PubMed] 53. Jiao, W.H.; Li, J.; Wang, D.; Zhang, M.M.; Liu, L.Y.; Sun, F.; Li, J.Y.; Capon, R.J.; Lin, H.W. Cinerols, nitrogenous meroterpenoids from the marine sponge Dysideacinerea. J. Nat. Prod. 2019, 82, 2586–2593. [CrossRef][PubMed] 54. Yu, H.B.; Yin, Z.F.; Gu, B.B.; Zhang, J.P.; Wang, S.P.; Yang, F.; Lin, H.W. Cytotoxic meroterpenoids from the marine sponge Dactylospongia elegans. Nat. Prod. Res. 2019, 1633644. [CrossRef] 55. Luo, X.C.; Li, P.L.; Wang, K.Y.; Voogd, N.J.; Tang, X.L.; Li, G.Q. Cytotoxic sesquiterpenoid quinones from South China Sea sponge Dysidea sp. Nat. Prod. Res. 2019, 1679132. [CrossRef] 56. Gui, Y.H.; Liu, L.; Wu, W.; Zhang, Y.; Jia, Z.L.; Shi, Y.P.; Kong, H.T.; Liu, K.C.; Jiao, W.H.; Lin, H.W. Discovery of nitrogenous sesquiterpene quinone derivatives from sponge Dysidea septosa with anti-inﬂammatory activity in vivo zebrafsh model. Bioorg. Chem. 2020, 94, 103435. [CrossRef] Molecules 2020, 25, 2485 30 of 32

57. Jiso, A.; Kittiwisut, S.; Chantakul, R.; Yuenyongsawad, S.; Putchakarn, S.; Schaberle, T.F.; Temkitthaworn, P.; Ingkaninan, K.; Chaithirayanon, K.; Plubrukarn, A. Quintaquinone, a merosesquiterpene from the yellow sponge Verongula cf. rigida Esper. J. Nat. Prod. 2020, 9b00886. 58. Che, Q.; Zhu, T.J.; Qi, X.; Attila, M.; Tibor, K.; Mo, X.M.; Li, J.; Gu, Q.Q.; Li, D.H. Hybrid isoprenoids from a reeds rhizosphere soil derived actinomycete Streptomyces sp. CHQ-64. Org. Lett. 2012, 14, 3438–3441. [CrossRef] 59. Zhang, Q.B.; Mándi, A.; Li, S.; Chen, Y.C.; Zhang, W.J.; Tian, X.P.; Zhang, H.B.; Li, H.X.; Zhang, W.M.; Zhang, S.; et al. N-N-coupled indolo-sesquiterpene atropo-diastereomers from a marine-derived actinomycete. Eur. J. Org. Chem. 2012, 27, 5256–5262. [CrossRef] 60. Suto, S.; Tanaka, N.; Fromont, J.; Kobayashi, J. Halichonadins G–J, new sesquiterpenoids from a sponge Halichondria sp. Tetrahedron Lett. 2011, 52, 3470–3473. [CrossRef] 61. Tanaka, N.; Suto, S.; Ishiyama, H.; Kubota, T.; Yamano, A.; Shiro, M.; Fromont, J.; Kobayashi, J. Halichonadins K and L, new dimeric sesquiterpenoids from a sponge Halichondria sp. Org. Lett. 2012, 14, 3498–3501. [CrossRef] [PubMed] 62. Tanaka, N.; Suto, S.; Asai, M.; Kusama, T.; Takahashi-Nakaguchi, A.; Gonoi, T.; Fromont, J.; Kobayashi, J. Halichonadins M–Q, sesquiterpenes from an Okinawan marine sponge Halichondria sp. Heterocycles 2015, 90, 173–185. 63. Ma, J.-H.; Zhao, F.; Wang, Y.; Liu, Y.; Gao, S.Y.; Ding, L.-Q.; Chen, L.X.; Qiu, F. Natural nitric oxide (NO) inhibitors from the rhizomes of Curcuma phaeocaulis. Org. Biomol. Chem. 2015, 13, 8349–8358. [CrossRef] [PubMed] 64. Wang, S.S.; Cheng, Y.B.; Lin, Y.C.; Liaw, C.C.; Chang, J.Y.; Kuo, Y.H.; Shen, Y.C. Nitrogen-containing diterpenoids, sesquiterpenoids, and nor-diterpenoids from Cespitularia taeniata. Mar. Drugs 2015, 13, 5796–5814. [CrossRef] 65. Prawat, H.; Mahidol, C.; Kaweetripo, W.; Prachyawarakorn, V.; Tuntiwachwuttikul, P.; Ruchirawat, S. Sesquiterpene isocyanides, isothiocyanates, thiocyanates, and formamides from the Thai sponge Halichondria sp. Tetrahedron 2016, 72, 4222–4229. [CrossRef] 66. Li, X.W.; Chen, S.H.; Ye, F.; Mollo, E.; Zhu, W.L.; Liu, H.L.; Guo, Y.W. Axiriabilines A-D, uncommon nitrogenous eudesmane-type sesquiterpenes from the Hainan sponge Axinyssa variabilis. Tetrahedron 2017, 73, 5239–5243. [CrossRef] 67. Wu, Q.H.; Chen, W.T.; Li, S.W.; Ye, J.Y.; Huan, X.J.; Gavagnin, M.; Yao, L.G.; Wang, H.; Miao, Z.H.; Li, X.W.; et al. Cytotoxic nitrogenous terpenoids from two South China Sea nudibranchs Phyllidiella pustulosa, Phyllidia coelestis, and their sponge-prey Acanthella cavernosa. Mar. Drugs 2019, 17, 56. [CrossRef] 68. Cai, Y.S.; Wu, Z.; Zheng, X.Q.; Wang, C.; Wang, J.R.; Zhang, X.X.; Qiu, G.F.; Zhu, K.K.; Cao, S.G.; Yu, J.Q. Spiroalanpyrroids A and B, sesquiterpene alkaloids with a unique spiro-eudesmanolide-pyrrolizidine skeleton from Inula helenium. Org. Chem. Front. 2020.[CrossRef] 69. Prawat, H.; Mahidol, C.; Wittayalai, S.; Intachote, P.; Kanchanapoom, T.; Ruchirawat, S. Nitrogenous sesquiterpenes from the Thai marine sponge Halichondria sp. Tetrahedron 2011, 67, 5651–5655. [CrossRef] 70. Abdjul, D.B.; Kanno, S.; Yamazaki, H.; Ukai, K.; Namikoshi, M. A dimeric urea of the bisabolene sesquiterpene from the Okinawan marine sponge Axinyssa sp. inhibits protein tyrosine phosphatase 1B activity in Huh-7 human hepatoma cells. Bioorg. Med. Chem. Lett. 2016, 26, 315–317. [CrossRef] 71. Sim, D.C.M.; Mudianta, I.W.; White, A.M.; Martiningsih, N.W.; Loh, J.J.M.; Cheney, K.L.; Garson, M.J. New sesquiterpenoid isonitriles from three species of phyllidid nudibranchs. Fitoterapia 2018, 126, 69–73. [CrossRef][PubMed] 72. Zhu, S.S.; Qin, D.P.; Wang, S.X.; Yang, C.; Li, G.P.; Cheng, Y.X. Commipholactam A, a cytotoxic sesquiterpenoidal lactam from Resina Commiphora. Fitoterapia 2019, 134, 382–388. [CrossRef][PubMed] 73. Liu, L.; Chen, X.Y.; Li, D.; Zhang, Y.; Li, L.; Guo, L.D.; Cao, Y.; Che, Y.S. Bisabolane sesquiterpenoids from the plant endophytic fungus Paraconiothyrium brasiliense. J. Nat. Prod. 2015, 78, 746–753. [CrossRef][PubMed] 74. Raiju, K.; Hitora, Y.; Kato, H.; Ise, Y.; Angkouw, E.D.; Mangindaan, R.E.P.; Tsukamoto, S. Halichonic acid, a new rearranged bisabolene-type sesquiterpene from a marine sponge Halichondria sp. Tetrahedron Lett. 2019, 60, 1079–1081. [CrossRef] Molecules 2020, 25, 2485 31 of 32

75. Xin, Y.; Xu, M.; Wang, Y.F.; Zheng, X.H.; Zhu, H.T.; Wang, D.; Yang, C.R.; Zhang, Y.J.Phyllanthacidoid U: A new N-glycosyl norbisabolane sesquiterpene from Phyllanthus acidus (L.) skeels. Nat. Prod. Res. 2020, 1712387. [CrossRef] 76. Park, H.W.; Lee, J.H.; Choi, S.U.; Baek, N.I.; Kim, S.H.; Yang, J.H.; Kim, D.K. Cytotoxic germacranolide sesquiterpenes from the bark of Magnolia kobus. Arch. Pharm. Res. 2020, 33, 71–74. [CrossRef] 77. Ohno, O.; Chiba, T.; Todoroki, S.; Yoshimura, H.; Maru, N.; Maekawa, K.; Imagawa, H.; Yamada, K.; Wakamiy, A.; Suenaga, K.; et al. Halichonines A, B, and C, novel sesquiterpene alkaloids from the marine sponge Halichondria okadai Kadota. Chem. Commun. 2011, 47, 12453–12455. [CrossRef] 78. Wang, C.Y.; Kim, D.; Zhu, Y.K.; Oh, D.C.; Huang, R.Z.; Wang, H.S.; Liang, D.; Lee, S.K. Glechomanamides A-C, 8 7 germacrane sesquiterpenoids with an unusual ∆ − ,12-lactam moiety from Salvia scapiformis and their antiangiogenic activity. J. Nat. Prod. 2019, 82, 3056–3064. [CrossRef] 79. Sugimoto, S.; Yamano, Y.; Desoukey, S.Y.; Katakawa, K.; Wanas, A.S.; Otsuka, H.; Matsunami, K. Isolation of sesquiterpene-amino acid conjugates, onopornoids A-D, and a flavonoid glucoside from Onopordum alexandrinum. J. Nat. Prod. 2019, 82, 1471–1477. [CrossRef] 80. Zhang, G.J.; Sun, S.W.; Zhu, T.J.; Lin, Z.J.; Gu, J.Y.; Li, D.H.; Gu, Q.Q. Antiviral isoindolone derivatives from an endophytic fungus Emericella sp. associated with Aegiceras corniculatum. Phytochem. 2011, 72, 1436–1442. [CrossRef] 81. Putz, A.; Kehraus, S.; Díaz-Agras, G.; Wägele, H.; König, G.M. Dotofide, a guanidine-interrupted terpenoid from the marine slug Doto pinnatifida (Gastropoda, Nudibranchia). Eur. J. Org. Chem. 2011, 3733–3737. [CrossRef] 82. Zhao, Z.B.; Sun, J.Z.; Mao, S.C.; Guo, Y.W. Fasciospyrinadine, a novel sesquiterpene pyridine alkaloid from a Guangxi sponge Fasciospongia sp. J. Asian Nat. Prod. Res. 2013, 15, 198–202. [CrossRef][PubMed] 83. Dong, L.M.; Huang, L.L.; Dai, H.; Xu, Q.L.; Ouyang, J.K.; Jia, X.C.; Gu, W.X.; Tan, J.W. Anti-MRSA sesquiterpenes from the semi-mangrove plant Myoporum bontioides A. Gray. Mar. Drugs 2018, 16, 438. [CrossRef][PubMed] 84. Ying, Y.M.; Shan, W.G.; Zhan, Z.J. Biotransformation of huperzine A by a fungal endophyte of Huperzia serrata furnished sesquiterpenoid-alkaloid hybrids. J. Nat. Prod. 2014, 77, 2054–2059. [CrossRef][PubMed] 85. Petersen, L.M.; Hoeck, C.; Frisvad, J.C.; Gotfredsen, C.H.; Larsen, T.O. Dereplication guided discovery of secondary metabolites of mixed biosynthetic origin from Aspergillus aculeatus. Molecules 2014, 19, 10898–10921. [CrossRef][PubMed] 86. Chen, C.J.; Liu, X.X.; Zhang, W.J.; Zang, L.Y.; Wang, G.; Seik, W.N.; Tan, R.X.; Ge, H.M. Sesquiterpenoids isolated from an endophyte fungus Diaporthe sp. RSC Adv. 2015, 5, 17559–17565. [CrossRef] 87. Zhang, L.H.; Feng, B.M.; Chen, G.; Li, S.G.; Sun, Y.; Wu, H.H.; Bai, J.; Hua, H.M.; Wang, H.F.; Pei, Y.H. SporulaminalsA and B: A pair of unusual epimericspiroaminal derivatives from a marine-derived fungus Paraconiothyrium sporulosum YK-03. RSC Adv. 2016, 6, 42361–42366. [CrossRef] 88. Wang, P.C.; Ran, X.H.; Luo, H.R.; Ma, Q.Y.; Zhou, J.; Hu, J.M.; Zhao, Y.X. Volvalerine A, an unprecedented N-containing sesquiterpenoid dimer derivative from Valeriana officinalis var. latifolia. Fitoterapia 2016, 109, 174–178. [CrossRef] 89. Song, Y.P.; Miao, F.P.; Yin, X.L.; Ji, N.Y. Nitrogenous cyclonerane sesquiterpenes from an algicolous strain of Trichoderma asperellum. Org. Chem. Front. 2019, 6, 3698–6704. [CrossRef] 90. Kim, D.; Lee, E.J.; Lee, J.; Leutou, A.S.; Shin, Y.H.; Choi, B.; Hwang, J.S.; Hahn, D.; Choi, H.; Chin, J.; et al. Antartin, a cytotoxic zizaane-type sesquiterpenoid from a Streptomyces sp. isolated from an Antarctic marine sediment. Mar. Drugs 2018, 16, 130. [CrossRef] 91. Fang, W.; Wang, J.J.; Wang, J.F.; Shi, L.Q.; Li, K.L.; Lin, X.P.; Min, Y.; Yang, B.; Tang, L.; Liu, Y.H.; et al. Cytotoxic and antibacterial eremophilane sesquiterpenes from the marine-derived fungus Cochliobolus lunatus SCSIO41401. J. Nat. Prod. 2018, 81, 1405–1410. [CrossRef][PubMed] 92. Shen, X.Y.; Qin, D.P.; Zhou, H.; Luo, J.F.; Yao, Y.D.; Lio, C.K.; Li, H.B.; Dai, Y.; Yu, Y.; Yao, X.S. Nardochinoids A-C, three dimeric sesquiterpenoids with specific fused-ring skeletons from Nardostachys chinensis. Org. Lett. 2018, 20, 5813–5816. [CrossRef][PubMed] 93. Wu, Z.L.; Wang, Q.; Wang, J.X.; Dong, H.Y.; Xu, X.K.; Shen, Y.H.; Li, H.L.; Zhang, W.D. Vlasoulamine A, a neuroprotective [3.2.2]cyclazine sesquiterpene lactone dimer from the roots of Vladimiria souliei. Org. Lett. 2018, 20, 7567–7570. [CrossRef][PubMed] Molecules 2020, 25, 2485 32 of 32

94. Wang, Q.; Hu, Z.Q.; Luo, X.C.; Liu, J.; Li, G.Q.; Cao, S.G.; Liu, Q.S. Clavukoellians A-F, Highly rearranged nardosinane sesquiterpenoids with antiangiogenic activity from Clavularia koellikeri. J. Nat. Prod. 2019, 82, 1331–1337. [CrossRef][PubMed] 95. Torii, M.; Kato, H.; Hitora, Y.; Angkouw, E.D.; Mangindaan, R.E.P.; Voogd, N.J.; Tsukamoto, S. Lamellodysidines A and B, sesquiterpenes isolated from the marine sponge Lamellodysidea herbacea. J. Nat. Prod. 2017, 80, 2536–2541. [CrossRef]

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