marine drugs

Review Structural Diversity, Biological Properties and Applications of Natural Products from Cyanobacteria. A Review †

Sayed Asmat Ali Shah 1,‡, Najeeb Akhter 1,‡, Bibi Nazia Auckloo 1, Ishrat Khan 1, Yanbin Lu 2, Kuiwu Wang 2, Bin Wu 1,* and Yue-Wei Guo 3,* ID 1 Ocean College, Zhejiang University, Hangzhou 310058, China; [email protected] (S.A.A.S.); [email protected] (N.A.); [email protected] (B.N.A.); [email protected] (I.K.) 2 Department of Applied Chemistry, Zhejiang Gongshang University, Hangzhou 310012, China; [email protected] (Y.L.); [email protected] (K.W.) 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China * Correspondence: [email protected] (B.W.); [email protected] (Y.-W.G.) Tel./Fax: +86-580-2092258 (B.W.); +86-21-50805813 (Y.-W.G.) † This review is dedicated to the memory of the late Professor Ernesto Fattorusso on the occasion of what would have been his 80th birthday. ‡ These two authors contributed equally to this article.

Received: 29 September 2017; Accepted: 3 November 2017; Published: 10 November 2017

Abstract: Nowadays, various drugs on the market are becoming more and more resistant to numerous diseases, thus declining their efficacy for treatment purposes in human beings. Antibiotic resistance is one among the top listed threat around the world which eventually urged the discovery of new potent drugs followed by an increase in the number of deaths caused by cancer due to chemotherapy resistance as well. Accordingly, marine cyanobacteria, being the oldest prokaryotic microorganisms belonging to a monophyletic group, have proven themselves as being able to generate pharmaceutically important natural products. They have long been known to produce distinct and structurally complex secondary metabolites including peptides, polyketides, alkaloids, lipids, and terpenes with potent biological properties and applications. As such, this review will focus on recently published novel compounds isolated from marine cyanobacteria along with their potential bioactivities such as antibacterial, antifungal, anticancer, anti-tuberculosis, immunosuppressive and anti-inflammatory capacities. Moreover, various structural classes, as well as their technological uses will also be discussed.

Keywords: cyanobacteria; secondary metabolites; biological properties and applications

1. Introduction Natural products have long been a source of unique and priceless molecules with potent pharmaceutical purposes, which are waiting to be further explored [1–3]. In the recent era, drug discoveries from marine sources have proved themselves as significant therapeutics where the isolation of effective marine compounds classified in various chemical classes is increasing annually [4,5]. As such, one vital source of these bioactive marine secondary metabolites is from marine microbes [6–9]. Cyanobacteria, also known as blue-green algae, are considered as an important group of ancient slow-growing photosynthetic prokaryotes, which are responsible for producing atmospheric oxygen as well as play a vital role in generating a surprisingly distinct group of secondary metabolites [10]. These marine microorganisms are known to live in a different environment, which could explain the chemical diversity of the compounds that have been isolated from them.

Mar. Drugs 2017, 15, 354; doi:10.3390/md15110354 www.mdpi.com/journal/marinedrugs Mar. Drugs 2017, 15, 354 2 of 30 Mar. Drugs 2017, 15, 354 2 of 29

Mostfrom them. of these Most metabolites of these metabolites are biologically are biological active andly areactive produced and are eitherproduced through either the through non-ribosomal the non- polypeptideribosomal polypeptide (NRP) or the (NRP) hybrid or the polyketide-NRP hybrid polyketide-NRP biosynthetic biosynthetic pathways. pathways. Their structural Their structural types are importanttypes are important subsets of subsets natural of products natural products possessing poss medicalessing medical capacities capacities such as such dolastatin as dolastatin 10 which 10 iswhich known is known as a tubulinas a tubulin polymerization polymerization inhibitor, inhibitor, the the vancomycin vancomycin antibiotic, antibiotic, cyclosporine cyclosporine asas anan immunosuppressant,immunosuppressant, bleomycin as a chemotherapy drug, and largazolelargazole and santacruzamatesantacruzamate A asas histone deacetylasedeacetylase inhibitorsinhibitors [[11–13].11–13]. Therefore, cyanobacteria have have been regarded as aa powerfulpowerful sourcesource ofof secondarysecondary metabolitesmetabolites withwith possiblepossible technologicaltechnological applicationsapplications in thethe pharmaceuticalpharmaceutical fieldfield leadingleading toto anan increaseincrease inin interestinterest inin thesethese researchresearch realmsrealms [[14].14]. In this scenario, until now an assortmentassortment of secondarysecondary metabolitesmetabolites such such as as peptides, peptides, polyketides, polyketides, alkaloids, alkaloids, lipids, lipids, and terpenes and terpenes [15] from [15] marine from cyanobacteriamarine cyanobacteria with potent with biological potent biological activities activities have been have isolated been isolated as shown as in shown Figure in1. Figure 1.

Figure 1. Biologically active secondary metabolites from marine cyanobacteria. Figure 1. Biologically active secondary metabolites from marine cyanobacteria.

Apart from producing toxins which can be utilized as pesticides in the agricultural field due to theirApart allelochemical from producing nature, toxins cyanobacteria which can behave utilized the asability pesticides to generate in the agricultural exceptional field bioactive due to theircompounds allelochemical that are nature, fascinating cyanobacteria in terms have theof ability their toantibacterial, generate exceptional antifungal, bioactive anti-cancerous, compounds thatimmunosuppressive, are fascinating in anti-inflammatory terms of their antibacterial, and anti-tub antifungal,erculosis anti-cancerous, activities [16–22]. immunosuppressive, As such, due to anti-inflammatoryincreased pharmaceutical and anti-tuberculosis values and applications, activities [ 16a new–22]. prospect As such, of due using to increased cyanobacteria pharmaceutical in the field valuesof medicine and applications,should be upgraded, a new prospect focusing of on using exploring cyanobacteria new taxonomic in the space field ofwhich medicine may provide should bean upgraded,advantage focusingregarding on unique exploring compound new taxonomic developme spacent. which As such, may providea large an number advantage of secondary regarding uniquemetabolite compound productions development. from cyanobacteria As such, a have large inci numberted investigators of secondary to metabolite engineer these productions organisms from in cyanobacteriaorder to achieve have highest incited production. investigators For toexample, engineer the these first organismscyanobacterium in order Synechocystis to achieve sp. highest PCC production.6803 underwent For full example, genome the sequencing first cyanobacterium by Kaneko etSynechocystis al., in 1996 [23].sp. Recently, PCC 6803 83% underwent enhancement full genomewas observed sequencing in ethanol by Kanekoproduction et al.,after in the 1996 pyruvate [23]. carboxylase Recently, 83% enzyme enhancement in Synechocystis was observed sp. PCC in6803 ethanol was engineered production after[24]. theMoreover, pyruvate a carboxylaseproject named enzyme CyanoGEBA in Synechocystis (Genomicsp. encyclopedia PCC 6803 was of engineeredBacteria and [ 24Archea)]. Moreover, was devised a project for namedgenome CyanoGEBA sequencing for (Genomic the identification encyclopedia of biosynthetic of Bacteria gene and Archea)clusters of was isolated devised known for genome compounds sequencing [25] which for therevealed identification that cyanobacteria of biosynthetic should gene be highlighted clusters of isolateddue its ability known to compoundsencode for several [25] which metabolite revealed gene that clusters. cyanobacteria On the other should hand, be highlightedthe advancement due itsin abilityanalytical to encode HPLC, for NMR several spectroscopy, metabolite genehigh clusters.throughput/high On the other content hand, screening the advancement and the inhyphenated analytical HPLC,techniques, NMR together spectroscopy, play a highsignificant throughput/high role in promoting content the screening new bioactive and the compounds hyphenated [26]. techniques, togetherThe playintensification a significant of rolemarine in promoting natural product the new stud bioactivey will likely compounds become [26 more]. notable, with the additionThe intensificationof innovative technologies of marine natural which product may help study for willthe likelyisolation become of compounds more notable, produced with the in additionscarce amount of innovative as well as technologies the capacity which to identify may helptheir forstructures. the isolation Comprehensively, of compounds state-of-the-art produced in scarcetechnologies amount along as well with as effective the capacity collaborations to identify be theirtween structures. academics Comprehensively, and industrial research state-of-the-art will be technologiesindispensable along to assure with the effective prospective collaborations success betweenof marine academics cyanobacterial and industrial secondary research metabolites will beas indispensableunique and groundbreaking to assure the prospective medicinal entities success for of marinethe therapy cyanobacterial of human secondarydisease. In metabolitesthis article, an as overview of various isolated secondary metabolites from cyanobacteria classified into different structural classes such as peptides, polyketides, alkaloids, and lipids along with their biological

Mar. Drugs 2017, 15, 354 3 of 30 unique and groundbreaking medicinal entities for the therapy of human disease. In this article, an overview of various isolated secondary metabolites from cyanobacteria classified into different structural classes such as peptides, polyketides, alkaloids, and lipids along with their biological properties and applications are discussed. That is, approximately one hundred recently published compounds with their structural diversity and absolute configuration including highlighted residues are given. These reported studies have great possibilities in contributing to the understanding and development of marine cyanobacterial natural products.

2. Chemical Diversity of Secondary Metabolites from Cyanobacteria The necessity of new compounds to be utilized as drugs has always been on the first row in pharmaceutical industries. Secondary metabolites that are isolated from cyanobacteria are of greater involvement due to their unique structural scaffolds and competency to produce potent drugs with significant biological properties such as antibacterial, antifungal, anticancer, anti-tuberculosis, immunosuppressive, and anti-inflammatory. According to Vijayakumar et al. and Mi et al., most of the secondary metabolites have been extracted from the genera Oscillatoriales, Lyngbya, Mooria, Okeania and Caldora [27,28]. However, the genera Moorea and Okeania were previously recognized, as has the polyphyly genus Lyngbya, while the genus Caldora was distinguished as Symploca. Until now, approximately 58% metabolites are reported from Oscillatoriales while 35% of natural products are reported from the genus Lyngbya. Therefore, marine cyanobacteria have attracted scientists from diverse areas including medicinal chemistry, pharmacology and marine chemical ecology. The different chemical classes, as well as potent biological properties of secondary metabolites isolated from cyanobacteria, are elaborated below.

2.1. Peptides Bioactive constituents from marine cyanobacteria have boosted attention in marine natural products research. The wide biologically active range of marine peptides from peptides–polyketides biosynthetic origin has high therapeutic potential which attracted pharmaceutical industries [29]. Study of these marine cyanobacteria has resulted in the development of a wealth of biologically active secondary metabolites, and the preponderance of these are peptides and peptide-derived compounds. Distinct structural classes of peptides such as linear peptides, linear depsipeptides, linear lipopeptides, cyclic peptides, cyclic depsipeptides, and cyclic lipopeptides have been previously discovered from marine cyanobacteria [30]. Notably, some cyanobacterial peptides and related hybrid metabolites have even proceeded as therapeutic lead compounds [20,29]. For example, brentuximab vedotin (trade name Adcetris), a marine peptide-derived medicine, was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma [31]. A summary of recently published secondary metabolites isolated from marine cyanobacteria is discussed below.

2.1.1. Cyclic Peptide Urumamide (1), a cyclic depsipeptide, was isolated from the marine cyanobacteria Okeania sp. collected from Ikei Island, Okinawa [32]. With accordance to the spectral analysis, urumamide contained seven α-amino acids (proline, valine, leucine, N-Me-isoleucine, N-Me-alanine, N-Me-leucine, and N-Me-valine), one α-hydroxy acid, a 2-hydroxy-isovaleric acid (Hiva), and one β-amino acid, (2S,3R)-Map. The absolute configuration of α-hydroxy acids (Hiva) was deduced by chiral HPLC analysis, assigning the stereochemistry as D-Hiva, while all α-amino acid residues were assigned L-form configuration using Marfey’s method. Urumamide (1) exhibited weak growth-inhibitory activity against human cancer cells with IC50 values of 18 ± 0.5 µM and 13 ± 0.5 µM, respectively (n = 3) as well as inhibited chymotrypsin with an IC50 value of 33 ± 9 µM(n = 3). Cyclic depsipeptide medusamide A (2), was isolated from a new genus of marine cyanobacterium, collected from Coiba Island on the Pacific coast of Panama [33]. Spectral analysis revealed the Mar. Drugs 2017, 15, 354 4 of 30 presence of four β-amino acids, one α-amino acid, and two α-hydroxy acid residues followed by representative residues being Amha 1–4, valine (Val), leucic acid (OLeu), and α-hydroxyisovaleric acid (Hiva). Subsequently, the absolute configuration of hydroxy acids deduced by chiral HPLC while using Marfey’s method for valine and Amha residues confirmed the stereochemistry as L-Hiva, D-OLeu, D-Valine and (2R,3R)-Amha respectively. Medusamide A (2) was found to be inactive against cancer cell growth. Odoamide (3), a cyclic depsipeptide containing a 26-membered ring was isolated from an Okinawan cyanobacterium genus Okeania sp. from Japan [34]. The spectral analysis suggested the presence of N-methyl alanine, isoleucine, N-methyl glycine, N-methyl phenylalanine, alanine, and 2-hydroxy-3-methylpentanoic acid (Hmpa) while the remaining structure was identified as 5,7-dihydroxy-2,6,8-trimethyl-undec-2-enoic acid (Dtuea). The absolute configuration of N-Me-Ala, Ile, N-Me-Phe and Ala residues were deduced by applying Marfey’s method and HPLC analysis, showing the arrangements as L, L, D, and L, respectively, and D-allo for Hmpa. Odoamide (3) showed moderate toxicity against brine shrimp with an LD50 value of 1.2 µM and potent cytotoxicity activity against HeLa S3 cells with an IC50 value of 26.3 nM. A cyclic depsipeptide, bouillonamide (4), was extracted from Moorea bouillonii collected from the northern coast of New Britain, Papua New Guinea [35]. Six partial structures were generated using spectroscopic analysis, which included two N-methyl phenylalanine residues, one N-methyl threonine residue, one valine residue, a 2-methyl-6-methylamino-hex-5-enoic acid (Mmaha) moiety, and a 3-methyl-5-hydroxy heptanoic acid (Mhha) unit. N-MePhe and Val residues were detected by Marfey’s method showing L-forms amino acids. Bouillonamide (4) showed moderate cytotoxic activity (IC50 of 6.0 µM) against neuro-2a mouse neuroblastoma cell line. Two new cyclic depsipeptides, companeramides A (5) and B (6), were isolated from marine cyanobacterial assemblage in Coiba National Park, Panama [36]. The presence of two N-methyl valine, one N-methyl leucine, one N-methyl alanine, one alanine (Ala), one proline (Pro) and two isoleucine (Ile) amino acid residues along with one hydroxyisovaleric acid (Hiva) followed by the presence of 3-amino-2-methyl-7-octynoic acid (Amoya) were confirmed by spectral analysis. On the other hand, companeramide B (6) revealed a similar structural composition to companeramide A (5), comprising of existing residues like Amoya, two N-Me-Val, Pro, Ile, and Hiva with a major difference suggesting that (6) had two Val spin systems. The absolute configuration of companeramide A (5) and B (6) residues were deduced as L-configuration for Ala, N-Me-Ala, Pro and both Ile, N-Me-Leu, N-Me-Val, and S-Hiva for companeramide A (5) while an L- and D-configuration was established as N-Me-L-Val, L-Val, N-Me-D-Ala (fragment 1), N-Me-L-Ala (fragment 2), and L-Pro for companeramide B (6). Companeramides A (5) and B (6) showed moderate anti-plasmodial activity (Figure2, Table1). Dudawalamides A–D (7–10), Dhoya-containing cyclic depsipeptides belonging to the kulolide superfamily, were isolated from Moorea producens, collected from Dudawali Bay, Papua New Guinea [37]. Dudawalamides A (7) consisted of six partial structures of amino acids and one Dhoya unit such as glycine, N-methyl-phenylalanine, N-Me-isoleucine, proline, alanine, lactic acid and a 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya). Moreover, the sequence of the residues were identified as cyclo-[Pro-N-Me-Phe-Gly-Dhoya-Lac-Ala-N-Me-Ile]. The absolute configuration was revealed as L-configuration for all residues like Lac, Ala, N-Me-Ile, and Pro, while R was assigned for Dhoya with an unusual D-configuration for the remaining residue N-Me-Phe. Dudawalamide B (8), was similar to dudawalamide A (7) with the only difference lies in the replacement of glycine, isoleucine, and lactic acid units in dudawalamide A by valine, and N,O-dimethyltyrosin units. The sequence of the residues were identified as cyclo-[Dhoya-Val-N-Me-Phe-Pro-N,O-diMe-Tyr-Ala]. Dudawalamide C (9) and D (10) were also an analog of dudawalamide A and were closely similar to each other. Both structures of dudawalamide C and D had similar amino acid residues excluding a hydroxy unit, such as Dhoya, valine, proline, N-methylphenylalanine, and glycine with a prominent difference showing the presence of a hydroxyisovaleric acid (Hiva) residue in dudawalamide C (9) and a 2-hydroxy-3-methylpentanoic acid (Hmpa) unit in dudawalamide D (10). The sequence of the residues was established as cyclo-[Dhoya-Val-N-Me-Val-Hiva-Pro-N-Me-Phe-Gly] Mar. Drugs 2017, 15, 354 5 of 30 and cyclo-[Dhoya-Val-N-Me-Val-Hmpa-Pro-N-Me-Phe-Gly], respectively. The unit Dhoya was deduced as S-configuration while the other amino acid residues as L-configuration and a hydroxy unit Hiva was established as L while the Hmpa unit was determined to be D-allo. Dudawalamide A (7) and D (10) showed potent activities against Plasmodium falciparum with IC50 values of 3.6 and 3.5 µM respectively. Moreover, D (8) showed effective activity against Leishmania donovani with an IC50 value of 2.6 µM. New cyclic depsipeptides, namely kohamamides A–C (11–13), belonging to the superfamily kulolide,Mar. Drugs isolated 2017, 15 from, 354 a cyanobacterium Okeania sp. and was collected in Japan [38]. Kohamamide5 of 29 A (11) wascyanobacterium seen to contain Okeania fivesp. and amino was collected acids residues in Japan [38]. with Kohamamide two hydroxy A (11 units) was seen including to contain alanine (Ala),five leucine amino (Leu), acids residues proline with (Pro), two valine hydroxy (Val), units methyl including ester alanine valine (Ala), (N leucine-Me-Val), (Leu), dimethyl proline (Pro), hydroxy octynoicvaline acid (Val), (Dhoya) methyl and ester 2-hydroxy-3-methylpentanoic valine (N-Me-Val), dimethyl hydroxy acid (Hmpa) octynoic with acid a sequence(Dhoya) and identified 2- as cyclo-[Dhoya-Ala-Leu-Pro-Hmpa-hydroxy-3-methylpentanoic acid (Hmpa)N-Me-Val-Val]. with a sequence The identified spectral as analysis cyclo-[Dhoya-Ala-Leu-Pro- also revealed that the KohamamidesHmpa-N-Me-Val-Val]. B and C (12 Theand spectral13) were analysis closely also similar revealed to A that (11 the) excluding Kohamamides the difference B and C (12 for and the 13 degree) of unsaturationwere closely ofsimilar the Dhoyato A (11 moiety.) excluding Kohamamide the difference B for (12 the) showed degree of potent unsaturation activity of against the Dhoya human moiety. Kohamamide B (12) showed potent activity against human cancer cells HL60 with an IC50 cancer cells HL60 with an IC50 value of 6.0 ± 2.1. The kohamamides A (11) and C (13) showed weak value of 6.0 ± 2.1. The kohamamides A (11) and C (13) showed weak activity against HL60 cells with activity against HL60 cells with IC50 values of 19 ± 3 and 11 ± 5, respectively. IC50 values of 19 ± 3 and 11 ± 5, respectively.

Val (2S, 3R)-Map H Amha-2 H H Amha-3 Leu N N N HN O NH O O Pro O O O O N Amha-4 Amha-1 HN N O O Hiva HN O O H N-Me-Ile O OLeu N NH N-Me-Val N O O N O O Val O O O N-Me-Leu N-Me-Ala Hiva

1 2

N-Me-Phe Ile NMe Phe-2 NMe Phe-1

N-Me-Gly NMe Thr O HO O N O N N N N Ala H O N O Mhha O N O N-Me-Ala O O HN O O OH O O NH Val N O O Mmaha O Hmpa Dtuea

34

N-Me-Ala-1 N-Me-Leu Val-1 O Pro Ala H O Pro H N N N N N N N O Ile-1 N O O O Ile-1 N-Me-Val-1 Fragment 1 O Fragment 1 O O O HN O HN O N-Me-Val-1 HN HN

O N O N O O N-Me-Val-2 O O N-Me-Val-2 O O Amoya N NH Amoya N Hiva NH Ile-2 Val-2 O Hiva N-Me-Ala Fragment 2 O N-Me-Ala Fragment 2

5 6 Figure 2. The chemical structures of: uramamide (1); medusamide A (2); odoamide (3); bouillonamide Figure 2. The chemical structures of: uramamide (1); medusamide A (2); odoamide (3); (4); companeramide A (5); and companeramide B (6). bouillonamide (4); companeramide A (5); and companeramide B (6). Viequeamides A (14) and B (15), a Dhoya-containing cyclic depsipeptides, were isolated from Rivularia sp. near Puerto Rico [39]. Viequeamide A (14) consisted of five partial structures of amino residues such as threonine, proline, valine, and two methyl esters valine along with Dhoya and Hmpa moieties, with the sequence cyclo-[Dhoya–Val-N-Me-Val-1–Hmpa–Pro-N-Me-Val-2-Thr]. The stereochemistry was established for all amino acid units as L-configuration, while Hmpa unit was established to be 2S, 3R, along with Dhoya unit bearing S configuration. The difference observed in B (15) was the presence of aryl protons, phenyl lactic acid (Pla), and N-methyl alanine. The

Mar. Drugs 2017, 15, 354 6 of 30

Viequeamides A (14) and B (15), a Dhoya-containing cyclic depsipeptides, were isolated from Rivularia sp. near Puerto Rico [39]. Viequeamide A (14) consisted of five partial structures of amino residues such as threonine, proline, valine, and two methyl esters valine along with Dhoya and Hmpa moieties, with the sequence cyclo-[Dhoya–Val-N-Me-Val-1–Hmpa–Pro-N-Me-Val-2-Thr]. The stereochemistry was established for all amino acid units as L-configuration, while Hmpa unit was established to be 2S, 3R, along with Dhoya unit bearing S configuration. The difference observed inMar. B Drugs (15 2017) was, 15, 354 the presence of aryl protons, phenyl lactic acid (Pla), and N-methyl6 of 29 alanine. The stereochemistry for amino acid units was proven to be L-configuration, while S configuration was assigned forstereochemistry phenyl lactic for acidamino and acid Dhoya units was units. proven Viequeamide to be L-configuration, A (14) showedwhile S configuration potent cytotoxic was activity assigned for phenyl lactic acid and Dhoya units. Viequeamide A (14) showed potent cytotoxic activity ± against H460against human H460 human lungcancer lung cancer cells cells with with an an IC IC5050 valuevalue of of60 60± 10 nM10 (Figure nM (Figure 3, Table3 1)., Table 1).

Figure 3. The chemical structures of: dudawalamides A–D (7–10); kohamamides A–C (11–13); and Figure 3. The chemical structures of: dudawalamides A–D (7–10); kohamamides A–C (11–13); viequeamides A (14) and B (15). and viequeamides A (14) and B (15). A cyclic depsipeptide named pitiprolamide (16), which was noted to be structurally related to dolastatin 16, along with four pitipeptolides C–F (17–20), which are analogs of pitipeptolides A and 16 A cyclicB, were depsipeptide isolated from Lyngbya named majuscula pitiprolamide collected from ( ),Piti which Bomb Holes, was Guam noted [40,41]. to be Pitiprolamide structurally related to dolastatin(16) comprised 16, along eight with amino four acid pitipeptolides residues, namely C–F proline (17 –1–420 ),(Pro), which valine are (Val), analogs dolaphenvaline of pitipeptolides A and B,(Dpv), were 2-hydroxy isolated isovaleric from Lyngbya acid (Hiva) majuscula and a unit ofcollected 2,2-dimethyl-3-hydroxyhexanoic from Piti Bomb Holes,acid (Dmhha), Guam [40,41]. Pitiprolamidebearing (16 the) sequence comprised as Pro1-Dpv-Pro2-Pro3-Hiva-Pro4-Val-Dmhha. eight amino acid residues, namely The absolute proline configuration 1–4 (Pro), was valine (Val), revealed as L-configuration for all proline units and Val unit, while Dmhha unit showed 3R, Hiva dolaphenvalineunit had (Dpv), an S and 2-hydroxy Dpv unit bear isovaleric 2S, 3R configuration. acid (Hiva) Pitipeptolide and a unit C of (17 2,2-dimethyl-3-hydroxyhexanoic) was a tetrahydro-analog acid (Dmhha),of previously bearing published the sequence pitipeptolide as Pro1-Dpv-Pro2-Pro3-Hiva-Pro4-Val-Dmhha.A [41] which consisted of five amino acid residues such The as absolute configurationvaline, was N-methyl revealed phenylalanine, as L-configuration proline, is foroleucine, all proline and glycine units andincluding Val unit,one α while-hydroxyl Dmhha unit showed 3Rmethylpentanoic, Hiva unit had acid (Hmpa) an S and with Dpv the completely unit bear saturated 2S, 3R fattyconfiguration. acid derived unit Pitipeptolide 2,2-dimethyl-3- C (17) was a tetrahydro-analog of previously published pitipeptolide A [41] which consisted of five amino Mar. Drugs 2017, 15, 354 7 of 30 acid residues such as valine, N-methyl phenylalanine, proline, isoleucine, and glycine including one α-hydroxyl methylpentanoic acid (Hmpa) with the completely saturated fatty acid derived unit 2,2-dimethyl-3-hydroxy oxtanoic acid (Dhoaa). Pitipeptolide D (18) was an analog of lower degree methylation of pitipeptolide A, containing the same residues as pitipeptolide C (17) excluding N-methyl group modification. Pitipeptolide E (19) and F (20) showed close similarity to each other with one missingMar. Drugs 2017 methylene, 15, 354 group. Moreover, pitipeptolide E (19) had Hmpa → Hiva7 displacement, of 29 while pitipeptolide F (20) had Ile → Val movement compared to pitipeptolide. All amino and hydroxy oxtanoic acid (Dhoaa). Pitipeptolide D (18) was an analog of lower degree methylation of α-hydroxypitipeptolide acids showed A, containingL-configuration the same whileresidues it wasas pitipeptolide proved that C (17 the) excluding fatty acid N-methyl derived group units showed S configurationmodification. as compared Pitipeptolide to E pitipeptolide (19) and F (20) showed A. Pitiprolamide close similarity (16 to) each showed other with weak one cytotoxic missing activity → against HCT116methylene colorectal group. Moreover, carcinoma pitipeptolide (IC50 33 E µ(M)19) andhad Hmpa MCF7 breast Hiva adenocarcinomadisplacement, while cell lines pitipeptolide F (20) had Ile → Val movement compared to pitipeptolide. All amino and α-hydroxy (IC50 33 µM). Moreover, pitiprolamide F (20) showed the highest potency in the disc diffusion assay acids showed L-configuration while it was proved that the fatty acid derived units showed S against Mycobacteriumconfiguration as tuberculosis compared to. pitipeptolide A. Pitiprolamide (16) showed weak cytotoxic activity Thornburgagainst etHCT116 al. [42 colorectal] discovered carcinoma new (IC apratoxin50 33 µM) and analogs, MCF7 breast namely, adenocarcinoma apratoxin cell H (lines21) and(IC50 apratoxin A sulfoxide33 µM). (22), Moreover, from Moorea pitiprolamide producens, F (20) showedin the Gulfthe highest of Aqaba, potency Redin the Sea.disc diffusion Both apratoxin assay against H (21) and apratoxin AMycobacterium sulfoxide (tuberculosis22) were. closely similar to the previously isolated compound apratoxin A with Thornburg et al. [42] discovered new apratoxin analogs, namely, apratoxin H (21) and apratoxin a differenceA sulfoxide in the replacement (22), from Moorea of prolineproducens, residue in the Gulf in apratoxinof Aqaba, Red A bySea.pipecolic Both apratoxin acid H (Pip) (21) and in apratoxin H(21). Asapratoxin for apratoxin A sulfoxide A sulfoxide (22) were closely (22), similar spectral to the analysis previously confirmed isolated compound the presence apratoxin of A oxidized with sulfur atom withina difference the thiazoline in the replacement residue. Marfay’s of proline analysisresidue in showedapratoxin theA by presence pipecolic acid of N (Pip)-Me- inL apratoxin-Ala, D-Cya for an H (21). As for apratoxin A sulfoxide (22), spectral analysis confirmed the presence of oxidized sulfur S configuration at α carbon, N-Me-L-Ile, and O-Me-L-Tyr for both compounds. Additionally, L-Pip was atom within the thiazoline residue. Marfay’s analysis showed the presence of N-Me-L-Ala, D-Cya for seen for apratoxinan S configuration H unit at and α carbon,L-Pro N-Me- for apratoxinL-Ile, and O-Me- A sulfoxide.L-Tyr for both Apratoxin compounds. H Additionally, (21) showed L-Pip significant cytotoxicitywas to seen human for apratoxin NCI-H460 H unit lung and cancer L-Pro cells for apratoxin with an ICA 50sulfoxide.value ofApratoxin 3.4 nM, H while (21) showed an IC50 value of 89.9 nM wassignificant noted cytotoxicity for apratoxin to human A sulfoxide NCI-H460 ( 22lung), revealingcancer cells with a nearly an IC50 36-fold value of reduction 3.4 nM, while in an cytotoxicity. Therefore,IC these50 value results of 89.9 showednM was noted that for apratoxin apratoxin cytotoxicityA sulfoxide (22 was), revealing sensitive a nearly to certain36-fold reduction modifications of in cytotoxicity. Therefore, these results showed that apratoxin cytotoxicity was sensitive to certain the moCysmodifications thiazoline of unit the (FiguremoCys thiazoline4, Table unit1). (Figure 4, Table 1).

Figure 4. The chemical structures of: pitiprolamide (16); pitipeptolides C–F (17–20); apratoxin H (21); Figure 4. The chemical structures of: pitiprolamide (16); pitipeptolides C–F (17–20); apratoxin H (21); and apratoxin A sulfoxide (22). and apratoxin A sulfoxide (22).

Mar. Drugs 2017, 15, 354 8 of 30 Mar. Drugs 2017, 15, 354 8 of 29

A new new bioactive bioactive cyclo cyclo octapeptide, octapeptide, samoamide samoamide A (23 A) was (23 )purified was purified from Symploca from Symplocasp. collectedsp. collectedin American inAmerican Samoa in Samoa2017 [43]. in 2017 The [43planar]. The structure planar structureof samoamide of samoamide A (23) consisted A (23) consisted of eight ofproteogenic eight proteogenic and unmodified and unmodified amino acid aminoresidues acid and residuesfinally was and resolved finally as was cyclic resolved Leu-Val-Phe(1)- as cyclic Leu-Val-Phe(1)-Pro(1)-Ile-Phe(2)-Pro(2)-Pro(3)Pro(1)-Ile-Phe(2)-Pro(2)-Pro(3) (cyc-LVFPIFPP). (cyc-LVFPIFPP). All amino residues All amino were residues revealed were to be revealed in L- toconfiguration. be in L-configuration. The proline The re prolinesidues were residues assigned were assigned as trans (Pro-1), as trans cis(Pro-1), (Pro-2)cis and(Pro-2) trans and (Pro-3)trans (Pro-3)due to duetheir to difference their difference in chemical in chemical shifts between shifts between the β- and the γβ--carbons.and γ-carbons. Samoamide Samoamide A (23) was A ( 23tested) was against tested againsta series of a seriescancer of cell cancer line in cell vitro, line includingin vitro, including NCI H-460 NCI human H-460 non-small-cell human non-small-cell lung cancer lung cells cancer with cellsan IC with50 value an of IC 1.150 value µM, HCT-116 of 1.1 µM, human HCT-116 colorectal human carcinoma colorectal cells carcinoma with an cellsIC50 value with anof 4.5 IC50 µM,value H125 of 4.5humanµM, lung H125 adenocarcinoma, human lung adenocarcinoma, MCF7 human breast MCF7 adenocarcinoma, human breast adenocarcinoma, LNCaP human prostate LNCaP humancancer, prostateOVC5 human cancer, ovarian OVC5 human cancer, ovarian U251N cancer, human U251N glioblastoma, human glioblastoma, PANC-1 human PANC-1 pancreatic human carcinoma pancreatic carcinomaepithelial like epithelial cells, CEM like cells, human CEM acute human lymphoblastic acute lymphoblastic leukemia, leukemia, and CFU-GM and CFU-GM progenitor progenitor cells of cellshuman of humangranulocytic granulocytic and monocytic and monocytic lineages. lineages. Samoamide Samoamide A (23) was A (found23) was broadly found cytotoxic broadly cytotoxic to many tocancer many lines cancer without lines any without remarkable any remarkable selectivity. selectivity. Lopez et al. Lopez [44] reported et al. [44 a] cyclic reported peptide, a cyclic wewakzole peptide, wewakzoleB (24), isolated B ( 24from), isolated Moorea fromproducensMoorea near producens Jeddah, nearSaudi Jeddah, Arabia. SaudiWewakzole Arabia. B was Wewakzole closely similar B was closelyto wewakzole similar and to wewakzole most likely and belonged most likely to the belonged cyanobactin to the class cyanobactin [45]. Wewakzole class [45]. B Wewakzole (24) consisted B (24 of) consistednine basic ofand nine three basic modified and three amino modified acid residues, amino acid including residues, glycine including (Gly), glycine isoleucine (Gly), (Ile), isoleucine alanine (Ile),(Ala × alanine 2), phenylalanine (Ala × 2), phenylalanine (Phe × 2), proline (Phe (Pro× 2), ×proline 3), oxazole (Pro (Oxz),× 3), oxazole and methyloxazole (Oxz), and methyloxazole (MeOxz × 2). (MeOxzThe absolute× 2). configuration The absolute analysis configuration revealed analysis that alanine, revealed phenylalanine, that alanine, phenylalanine,proline, and isoleucine proline, andresidues isoleucine were in residues the L-configuration. were in the L-configuration. Wewakzole B ( Wewakzole24) showed Bpotent (24) showed toxicity potent against toxicity human against H460 humanlung cancer H460 cells lung (IC cancer50 1.0 cells µM) (IC and50 1.0moderateµM) and toxicity moderate against toxicity human against MCF7 human breast MCF7 cancer breast cells cancer (IC50 cells0.58 (ICµM).50 0.58OdobromoamideµM). Odobromoamide (25), a terminal (25), a terminal alkynyl alkynyl bromide-containing bromide-containing cyclodepsipeptide cyclodepsipeptide was wasisolated isolated from fromOkeaniaOkeania sp. in sp.Japan in [46]. Japan The [46 sequence]. The sequence of odobromoamide of odobromoamide (25) was arranged (25) was arrangedas N-Me- asVal-Pro-Val-N-Me-Val-Pro-Val-N-Me-Ile-Hmba-Br-(Hmoya)N-Me-Ile-Hmba-Br-(Hmoya) where the where absolute the configuration absolute configuration was seen to was be L seen-form to for be allL-form amino for acid all amino and Hmba acid andresidues. Hmba Finally residues., the Finally, stereostructure the stereostructure of odobromoamide of odobromoamide (25) was deduced (25) was deducedas 2S, 8S, as13 2SS, ,18 8SS,, 1319SS,, 1825SS,, 1930SS, 25andS, 3031SR.and Odobromoamide 31R. Odobromoamide (25) exhibited (25) exhibited potent cytotoxic potent cytotoxic activity activityagainst HeLa against S3 HeLa cells with S3 cells an withIC50 value an IC 50of value0.31 µM of 0.31(FigureµM 5, (Figure Table5 1)., Table 1).

Figure 5. The chemical structures of: samoamide A ( 23), wewakzole B ( 24) and odobromoamide (25).

Five new cyclic hexapeptides, anabaenopeptins (26–30), was isolated from the extract of Five new cyclic hexapeptides, anabaenopeptins (26–30), was isolated from the extract of cyanobacterial bloom material composed of Nodularia spumigena, Aphanizomenon flos-aquae and cyanobacterial bloom material composed of Nodularia spumigena, Aphanizomenon flos-aquae and Dolichospermum sp. from the Baltic Sea [47]. According to mass spectrum analysis, anabaenopeptin Dolichospermum sp. from the Baltic Sea [47]. According to mass spectrum analysis, anabaenopeptin NP NP 883 (26) contained (Ile + CO [Lys + Val+ Hph + MeHty + MetO]), anabaenopeptin NP 869 (27) 883 (26) contained (Ile + CO [Lys + Val+ Hph + MeHty + MetO]), anabaenopeptin NP 869 contained (Phe + CO [Lys + Val+ Leu + MeHty + MetO]), anabaenopeptin NP 867 (28) contained (Ile (27) contained (Phe + CO [Lys + Val+ Leu + MeHty + MetO]), anabaenopeptin NP 867 + CO[Lys + Val + Hph + MeHty + Met]), anabaenopeptin NP 865 (29) contained (Ile + CO[Lys + Val + (28) contained (Ile + CO[Lys + Val + Hph + MeHty + Met]), anabaenopeptin NP 865 (29) Hph + MeHty + AcSer]) and anabaenopeptin NP 813 (30) contained (Phe + CO[Lys + Val + Hty + contained (Ile + CO[Lys + Val + Hph + MeHty + AcSer]) and anabaenopeptin NP 813 (30) contained MeGly + Phe]). Most of them belonged to the subclass nodulapeptins when considering Met, Meto or (Phe + CO[Lys + Val + Hty + MeGly + Phe]). Most of them belonged to the subclass nodulapeptins AcSer in position 6. No activity was determined for these compounds (Figure 6, Table 1).

Mar. Drugs 2017, 15, 354 9 of 30 when considering Met, Meto or AcSer in position 6. No activity was determined for these compounds (FigureMar.6, Drugs Table 20171)., 15, 354 9 of 29

FigureFigure 6. 6.The The chemical chemical structuresstructures of anabaenopeptins anabaenopeptins (26 (–2630–).30 ).

2.1.2. Linear Peptides 2.1.2. Linear Peptides A linear depsipeptide, maedamide (31), isolated from the species of Lyngbya, was collected from AOkinawa linear Prefecture depsipeptide, [48]. Maedamide maedamide retained (31), isolated many important from the amino species acid of residuesLyngbya, suchwas as collecteda 4- fromamino-3-hydroxy-5-phenylpent Okinawa Prefecture [48]. Maedamideanoic acid retained(Ahppa), manyallo-D-isoleucine, important and amino N-Me- acidD-phenylalanine, residues such as a 4-amino-3-hydroxy-5-phenylpentanoicalong with two hydroxy acid moieties. acidSpectral (Ahppa), analysis allo- revealedD-isoleucine, the presence and ofN valic-Me- acid,D-phenylalanine, isoleucic alongacid, with proline, two hydroxyisoleucine, acid glycine, moieties. N-Me-phenylalanine, Spectral analysis and revealedO-Me-proline the presencewhile chiral of HPLC valic acid, isoleucicestablished acid, proline,the stereochemistry isoleucine, as L glycine,, allo-D, L,N allo--Me-phenylalanine,D, D, and L, respectively. and MaedamideO-Me-proline (31) inhibited while chiral the growth of human cancer cells and selectively inhibited chymotrypsin with the IC50 value of 45 HPLC established the stereochemistry as L, allo-D, L, allo-D, D, and L, respectively. Maedamide (31) µM. Meanwhile, maedamide showed strong protease inhibitory activity against chymotrypsin. A inhibited the growth of human cancer cells and selectively inhibited chymotrypsin with the linear pentapeptide, caldoramide (32), an analog of belamide A and dolastatin 15 (33), was isolated IC value of 45 µM. Meanwhile, maedamide showed strong protease inhibitory activity against 50 from Caldora penicillata in Florida [49]. Caldoramide consisted of one OMe, N,N-dimethylvaline, chymotrypsin.valine, N-Me A valine, linear N-Me pentapeptide, isoleucine, a caldoramideputative phenylalanine (32), an and analog a conjugated of belamide enol ether A and residues. dolastatin 15 (33The), combined was isolated data established from Caldora the structure penicillata of caldoramidein Florida as [49 N,N].-diMe-Val-Val- CaldoramideNMe-Ile-3- consistedO-Me- of one OMe,4-benzylpyrrolinoneN,N-dimethylvaline, and valine,the L-configurationN-Me valine, observedN-Me isoleucine,for all amino a putativeacids. Caldoramide phenylalanine (32) and a conjugateddisplayed enolanti-proliferative ether residues. activity The upon combined cells including data established oncogenic the KRAS structure or HIF of transcription caldoramide as

Mar. Drugs 2017, 15, 354 10 of 30

N,N-diMe-Val-Val-NMe-Ile-3-O-Me-4-benzylpyrrolinone and the L-configuration observed for all amino acids. Caldoramide (32) displayed anti-proliferative activity upon cells including oncogenic KRAS or HIF transcription factors, namely, parental HCT 116 over HCT 116HIF-1α−/−HIF-2α−/− and HCT 116WT KRAS. Three lipopeptides, tasiamides C–E (33–35), were isolated from Symploca sp. near Kimbe Bay, Papua New Guinea [50]. Tasiamide C (33) consisted of five amino and two hydroxy acid residues like proline methyl ester (N-MePro), phenylalanine methyl ester (N-MePhe), alanine (Ala),Mar. Drugs isoleucine 2017, 15, 354 (Ile), glutamine methyl ester (N-MeGln), and two 2-hydroxy-3-methylbutyric10 of 29 acids (Hmba),factors, indicating namely, parental an overall HCT 116 linear over HCT arrangement. 116HIF-1α−/−HIF-2α− Three/− and HCT amino 116WT acids KRAS. Three (Pro, lipopeptides, Ala and N-MeGln) were L-configuration,tasiamides C–E (N33-MePhe–35), were wasisolatedD-configuration from Symploca sp. andnear KimbeD-allo Bay, configuration Papua New Guinea of Ile [50]. residue was assigned forTasiamide tasiamide C (33) C.consisted The two of five Hmba amino stereo-centers and two hydroxy suggested acid residues that like proline the absolute methyl ester configuration (N- of this compoundMePro), was phenylalanine 2S, 8R, 18methylS, 21 esterR, 22 (NS-MePhe),, 27S, 33 alanineR, and (Ala), 38S isoleucine. Tesiamide (Ile), glutamine D (34) resulted methyl ester in the loss of (N-MeGln), and two 2-hydroxy-3-methylbutyric acids (Hmba), indicating an overall linear N-methylarrangement. on the phenylalanine Three amino acids (Phe) (Pro, residue, Ala and thus N-MeGln) proving were an L-configuration, arrangement N-MePhe of N-MePro, was D- Phe, Ala, Ile, N-MeGln,configuration Hmba-1, and and D-allo Hmba-2 configuration with of the Ile absoluteresidue was configuration assigned for tasiamide being 2C.S ,The 8R ,two 17 SHmba, 20S , 21S, 26S, 32R, and 37stereo-centersS. The presence suggested of that one the additional absolute configuration amino acid of this residue compound leucine was 2 (Leu)S, 8R, 18 andS, 21 aR, hydroxyl22S, unit 2-hydroxy-4-methylpentanoic27S, 33R, and 38S. Tesiamide acid (H4mpa)D (34) resulted in tesiamide in the loss Eof (N35-methyl) differentiated on the phenylalanine it from tesiamide (Phe) C and residue, thus proving an arrangement of N-MePro, Phe, Ala, Ile, N-MeGln, Hmba-1, and Hmba-2 D with thewith absolute the absolute configuration configuration being being 22SS,, 8R, ,17 20S,S 20, 21S, S21,S 26, 26SS,, 32 32SR,, andand 37 38S.S The. presence of one Tesiamideadditional F ( 36amino), an acid analog residue of leucine tesiamide (Leu) and B, a was hydroxyl isolated unit 2-hydroxy-4-methylpentanoic from cyanobacterial species acid Lyngbya, from Guam(H4mpa) [51]. in As tesiamide compound E (35) differentiated tesiamide it Ffrom was tesiamide an analog C and ofD with the the previously absolute configuration isolated tesiamide B, the differencebeing 2S, 8 liesR, 20S in, 21 theS, 26S replacement, 32S, and 38S. of amino acid residues in tesiamide B to Ala → Gly, Tesiamide F (36), an analog of tesiamide B, was isolated from cyanobacterial species Lyngbya, Leu → Ilefrom, Val Guam→ Ile, [51]. with As compound the presence tesiamide of a statinF was an unit analog Ahppa of the (Aminopreviously hydroxyphenyl isolated tesiamide pentanoicB, the acid) differing itdifference from other lies in tesiamidethe replacement structures. of amino acid Tasiamides residues in C tesiamide (33) and B to D Ala (34 →) wereGly, Leu found → Ile,to Val be inactive → Ile, with the presence of a statin unit Ahppa (Amino hydroxyphenyl pentanoic acid) differing it against the HCT-116 colon cancer cell line (tasiamide C, IC50 > 25 µM; tasiamide D, IC50 ≈ 25 µM). The anti-proteolyticfrom other tesiamide activity structures. of tesiamide Tasiamides F C (36 (33)) wasand D evaluated (34) were foundin vitroto be inactiveagainst against cathepsins the D, E, HCT-116 colon cancer cell line (tasiamide C, IC50 > 25 µM; tasiamide D, IC50 ≈ 25 µM). The anti- and BACE1proteolytic (an enzyme activity of involved tesiamide F in (36 the) was pathogenesis evaluated in vitro of against Alzheimer’s cathepsins disease), D, E, and BACE1 which (an revealed a low nanomolarenzyme inhibitory involved in activity. the pathogenesis Compound of Alzheimer’s tesiamide disease), F was which considered revealed less a low potent nanomolar against BACE1. inhibitory activity. Compound tesiamide F was considered less potent against BACE1. Additionally, Additionally, tasiamide and tasiamide B showed moderate cytotoxicity against KB cells, with IC50 values of 0.48tasiamide and and 0.8 µtasiamideM, respectively B showed moderate (Figure7 cytotoxicity, Table1). against KB cells, with IC50 values of 0.48 and 0.8 µM, respectively (Figure 7, Table 1).

Figure 7. The chemical structures of: maedamide (31); caldoramide (32); tasiamides C–E (33–35); and Figure 7. The chemical structures of: maedamide (31); caldoramide (32); tasiamides C–E (33–35); tasiamide F (36). and tasiamide F (36). Mar. Drugs 2017, 15, 354 11 of 30 Mar. Drugs 2017, 15, 354 11 of 29

Two new antifungal linear lipopeptides, balticidin A (37) and C (38), and two new cyclic analog Two new antifungal linear lipopeptides, balticidin A (37) and C (38), and two new cyclic analog balticidin B (39) and D (40) were extracted from Anabaena cylindrica collected from the Baltic Sea, balticidin B (39) and D (40) were extracted from Anabaena cylindrica collected from the Baltic Sea, Rügen Island, Germany [52]. Balticidin A consisted of nine amino acid residues such as threonine Rügen Island, Germany [52]. Balticidin A consisted of nine amino acid residues such as threonine (Thr) (Thr × 3), dehydroamino butyric acid (Dhb), glutamic acid (Glx) (Glx × 2), glycine (Gly), β- (Thr) (Thr × 3), dehydroamino butyric acid (Dhb), glutamic acid (Glx) (Glx × 2), glycine (Gly), hydroxytyrosine (possessed AA’BB’ spin system), N-Me-Thr (spin system lacking an amide proton) β-hydroxytyrosine (possessed AA’BB’ spin system), N-Me-Thr (spin system lacking an amide proton) and β-HOTyr. Spectrometric data also revealed the presence of chlorinated dihydroxy (10-DhA) fatty and β-HOTyr. Spectrometric data also revealed the presence of chlorinated dihydroxy (10-DhA) acid moiety and three anomeric protons which proved the presence of three sugar moieties. The fatty acid moiety and three anomeric protons which proved the presence of three sugar moieties. configuration of these monosaccharides was established as D(+)-mannose, D(−)-arabinose and D(+)- The configuration of these monosaccharides was established as D(+)-mannose, D(−)-arabinose and galacturonic acid. Balticidin C (38) showed the difference in an aliphatic chain where it contained D(+)-galacturonic acid. Balticidin C (38) showed the difference in an aliphatic chain where it contained hydrogen instead of chlorine in the side chain attached to the first threonine unit. Balticidin D (40) hydrogen instead of chlorine in the side chain attached to the first threonine unit. Balticidin D (40) was seen to be in close similarity with balticidin B showing the difference in hydrogen excluding the was seen to be in close similarity with balticidin B showing the difference in hydrogen excluding chlorine on the fatty acid residue. Balticidins A–D (37–40) showed active inhibition zone against the chlorine on the fatty acid residue. Balticidins A–D (37–40) showed active inhibition zone against Candida maltose with 12, 15, 9 and 18 mm, respectively (Figure 8, Table 1). Candida maltose with 12, 15, 9 and 18 mm, respectively (Figure8, Table1).

FigureFigure 8. The 8. The chemical chemical structure structure of ofbalticidins balticidins A–D A–D (37 (37–40–40). ).

In 2014, a draft genome of Anabaena sp. SYKE748A was obtained and reported as responsible for the production of numerous unique glycosylated lipopeptides [53]. Thus, hassallidins C (41) and D

Mar. Drugs 2017, 15, 354 12 of 30

In 2014, a draft genome of Anabaena sp. SYKE748A was obtained and reported as responsible for the production of numerous unique glycosylated lipopeptides [53]. Thus, hassallidins C (41) and D (Mar.42), Drugs which 2017, resemble 15, 354 previously isolated antifungal hassallidins A and B, separated12 of 29 from an epilithic cyanobacterium Hassallia sp. [54]. Spectral analysis confirmed the presence of nine amino (42), which resemble previously isolated antifungal hassallidins A and B, separated from an epilithic acid residues, namely, threonine (Thr × 3), tyrosine (Tyr × 2), glutamine (Gln × 2), glycine (Gly), cyanobacterium Hassallia sp. [54]. Spectral analysis confirmed the presence of nine amino acid and N-methylresidues, threonine namely, threonine (N-MeThr) (Thr along× 3), tyrosine with one (Tyr 2,3-dihydroxy × 2), glutamine fatty(Gln × acid, 2), glycine and three (Gly), sugar and N moieties- with configurationmethyl threonineL-Thr, (N-MeThr)D-Thr, alongD-allo-Thr, with oneD -Tyr,2,3-dihydroxyD-Gln, Gly,fatty Nacid,-MeThr, and threeL-Gln, sugar and moietiesL-Tyr. with The main differenceconfiguration in both structuresL-Thr, D-Thr, was D-allo-Thr, observed D-Tyr, at positionD-Gln, Gly, 10, N as-MeThr, in hassallidin L-Gln, and CL-Tyr. (41) The with main glutamine (L-Gln)difference while hassallidin in both structures D (42 )was with observed tyrosine at position (L-Tyr). 10, as Both in hassallidin compounds C (41) inhibited with glutamine the growth(L- of Gln) while hassallidin D (42) with tyrosine (L-Tyr). Both compounds inhibited the growth of Candida Candida albicans. Hassallidin D was active against Candida albicans and Candida krusei with MIC albicans. Hassallidin D was active against Candida albicans and Candida krusei with MIC value ≤ 2.8 ≤ µ µ ≤ µ value µg/mL2.8 g/mL (1.5 µM). (1.5 Interestingly,M). Interestingly, the linear theform linear of hassallidin form of C hassallidin had an MIC C of had ≤36 an µg/mL MIC (20 of µM),36 g/mL (20 µM),indicating indicating the thesignificance significance of the ofring the structur ringe structure for antifungal for antifungalactivities (Figure activities 9, Table (Figure 1). 9, Table1).

Figure 9. Chemical structure of Hassallidins C–D (41–42). Figure 9. Chemical structure of Hassallidins C–D (41–42). A newA acetylene-containing new acetylene-containing lipopeptide, lipopeptide, kurahynekurahyne (43 (43), ),was was obtained obtained from froma cyanobacterial a cyanobacterial collectioncollection that mostlythat mostly consisted consisted of LyngbyaLyngbya sp. sp.from Kuraha, from Kuraha,Okinawa [55]. Okinawa Kurahyne [55 (43].) contained Kurahyne (43) seven residues including one proline, two N-methyl valines, two N-methyl isoleucines, one 2-(1-oxo- contained seven residues including one proline, two N-methyl valines, two N-methyl propyl)-pyrrolidine (Opp) and a 2-methyloct-2-en-7-ynoic acid (Moya). The stereochemistry isoleucines,indicated one L-configuration 2-(1-oxo-propyl)-pyrrolidine for all amino acids in (Opp) kurahy andne, while a 2-methyloct-2-en-7-ynoic the absolute configuration in acid Opp (Moya). The stereochemistrymoiety was elucidated indicated to be L4S-configuration. Kurahyne was observed for all amino to hinder acids the growth in kurahyne, of both HeLa while cells the and absolute configurationHL60 cells in Oppwith IC moiety50 values was of 3.9 elucidated ± 1.1 µM toand be 1.5 4 S±. 0.1 Kurahyne µM sequentially. was observed Kurahyne to B hinder (44), a new the growth analog of kurahyne (43), was isolated from the marine cyanobacterium Okeania sp. near Jahana, of both HeLa cells and HL60 cells with IC50 values of 3.9 ± 1.1 µM and 1.5 ± 0.1 µM sequentially. KurahyneOkinawa B (44 [56].), a newKurahyne analog B was of kurahyneseen to have ( 43one), wasN-methylisoleucine isolated from and the one marine isoleucine, cyanobacterium while kurahyne (43) had two N-methylisoleucines. Kurahyne B (44) repressed the growth of human cancer Okeania N cellssp. to near the same Jahana, extent Okinawa as kurahyne [56 (].43). Kurahyne An acetylene B containing was seen lipopeptide, to have one Jahanyne-methylisoleucine (45) was and oneisolated isoleucine, from Lyngbya while kurahynesp. near Jahana, (43) hadOkinawa two [57].N-methylisoleucines. The structure consisted Kurahyne of seven amino B (44 )acid repressed the growthresidues of humanwith one 2-(1-oxo-ethyl)-pyrrolidine cancer cells to the same unit extent (Oep) and as kurahyne2,4-dimethyldec-9-ynoic (43). An acetylene acid (fatty acid containing lipopeptide,unit). The Jahanyne sequence (45 of) jahanyne was isolated was arranged from Lyngbya as Pro1-Oep-sp.N near-Me-Phe- Jahana,N-Me-Val1- OkinawaN-Me-Val2- [57]. TheN-Me- structure consistedVal3-Pro2- of sevenN-Me-Ala-Fatty amino acid acid. residues The absolute with configuration one 2-(1-oxo-ethyl)-pyrrolidine was assigned to be L form to unit all amino (Oep) and acid residues, while the Oep configuration as 3R. The absolute configuration of a fatty acid moiety 2,4-dimethyldec-9-ynoic acid (fatty acid unit). The sequence of jahanyne was arranged as was determined as 2R. Jahanyne significantly inhibited the growth of HeLa cells and HL60 cells, with Pro1-Oep-N-Me-Phe-N-Me-Val1-N-Me-Val2-N-Me-Val3-Pro2-N-Me-Ala-Fatty acid. The absolute IC50 values of 1.8 µM and 0.63 µM, respectively. configurationKanamienamide was assigned (46), to an be enamideL form with to allan enol amino ether acid 11-membered residues, lipopeptide, while the isolated Oep configuration from as 3R. TheMoorea absolute bouillonii configuration, was collected of in a Kagoshima fatty acid [58]. moiety Spectral was analysis determined exposed as 2theR. presence Jahanyne of significantlyeight methyl groups as well as proved the presence of three partial structures. Likewise, kanamienamide inhibited the growth of HeLa cells and HL60 cells, with IC50 values of 1.8 µM and 0.63 µM, respectively. Kanamienamide (46), an enamide with an enol ether 11-membered lipopeptide, isolated from Moorea bouillonii, was collected in Kagoshima [58]. Spectral analysis exposed the presence of eight Mar. Drugs 2017, 15, 354 13 of 30 methyl groups as well as proved the presence of three partial structures. Likewise, kanamienamide was composedMar. Drugs 2017 of, 15N, 354-methylleucine, 7-hydroxy-2,4-dimethyl-12-(methylamino)-dodec-11-enoic13 of 29 acid and 3-methoxy-2-pentenoic acid. The geometries of two olefins were determined to be Z and E, was composed of N-methylleucine, 7-hydroxy-2,4-dimethyl-12-(methylamino)-dodec-11-enoic acid respectively with the relative stereochemistry being 2’S,2R,4S,7S. Kanamienamide (46) exhibited and 3-methoxy-2-pentenoic acid. The geometries of two olefins were determined to be Z and E, µ growth-inhibitoryrespectively with activity the relative in HeLa stereochemistry cells with IC being50 2.5 2’S,2MR,4 andS,7S. caused Kanamienamide apoptosis-like (46) exhibited cell death in HeLagrowth-inhibitory cells. It was suggested activity in HeLa that kanamienamidecells with IC50 2.5 µM (46 and) might caused have apoptosis-like at least two cell death target in moleculesHeLa for causingcells. It was apoptosis-like suggested that cell kanamienamide death by upstream (46) might of have caspases, at least downstream two target molecules of caspases for causing and other pathways.apoptosis-like Thiazole cell containing death by upstream lipopeptides, of caspases, biseokeaniamides downstream of A–C caspases (47– 49and), wereother identifiedpathways. and purifiedThiazole from containing the Japanese lipopeptides, cyanobacterial biseokeaniamidesOkeania sp. A–C [59]. (47 Biseokeaniamide–49), were identified A consisted and purified of five from amino acid residuesthe Japanese including cyanobacterial two methyl Okeania valinessp. [59]. Biseokeaniamide ester, methyl phenylalanine A consisted of five ester, amino proline, acid residues and leucine withincluding a thiazole two ring methylN-methyl-2-thiazolemethane-amine valines ester, methyl phenylalanine ester, (Thz- proline,N-Me-Gly) and leucine and butanoicwith a thiazole acid (Ba). ring N-methyl-2-thiazolemethane-amine (Thz-N-Me-Gly) and butanoic acid (Ba). The absolute The absolute configuration of A was seen as L form for all amino acid residues. Biseokeaniamides B configuration of A was seen as L form for all amino acid residues. Biseokeaniamides B (48) and C (49) (48) and C (49) were found to be in close similarity to biseokeaniamide A, and were determined to be an were found to be in close similarity to biseokeaniamide A, and were determined to be an N-demethyl N-demethylanalog of analog A. The ofdifference A. The differenceobserved in observed both compounds in both was compounds the absence was of two the N absence-methyl ofgroups. two N The-methyl groups.sequence The sequenceof B (48) ofwas B (noted48) was as notedBa-N-Me-Val-Pro- as Ba-N-Me-Val-Pro-N-Me-Phe-Leu-Val-Thz-N-Me-Phe-Leu-Val-Thz-N-Me-Gly whileN -Me-Glythe whilesequence the sequence of C of ( C49 ()49 )was was arranged arranged as Ba-Val-Pro-Ba-Val-Pro-N-Me-Phe-Leu--Me-Phe-Leu-N-Me-Val-Thz-N-Me-Val-Thz-N-Me-Gly.N-Me-Gly. BiseokeaniamideBiseokeaniamide B exhibitedB exhibited growth inhibitory inhibitory activity activity against against HeLa cells HeLa with cells an IC with50 value an of IC 4.550 µM.value of 4.5 µM.Biseokeaniamides Biseokeaniamides A–C A–Cinhibited inhibited sterol O sterol-acyltransferaseO-acyltransferase SOAT1 and SOAT1 SOAT2 and with SOAT2 IC50 values with IC of50 1.8values µM, 1.3 µM, 6.9, 1.3 µM, and >12, 9.6 µM, respectively, on cellular level and with IC50 values of 1.8 µM, of 1.8 µM, 1.3 µM, 6.9, 1.3 µM, and >12, 9.6 µM, respectively, on cellular level and with IC50 values of 1.8 µM,9.6 9.6µM,µ 6.8M, µM, 6.8 9.9µM, µM, 9.9 andµM, 11, and >32 11,µM, >32 respectively,µM, respectively, on enzymatic on enzymaticlevel (Figure level 10, Table (Figure 1). 10, Table1).

FigureFigure 10. Chemical 10. Chemical structures structures of: kurahyne of: kurahyne (43); kurahyne (43); kurahyne B (44); jahanyne B (44); (45 jahanyne); and biseokeaniamides (45); and A–C (biseokeaniamides47–49). A–C (47–49).

Furthermore, a new lipopeptide, namely maylngamide (50), isolated from Moorea producens, was Furthermore,collected in Hawaii a new [60]. lipopeptide,Maylngamide namely(50) showed maylngamide the existence (of50 a), linear isolated alkyl fromgroup,Moorea olefin moiety producens , was collectedalong with inhydroxyl Hawaii group, [60]. two Maylngamide methoxy groups, (50 an) showedN-methyl themoiety, existence presence of of a chloromethylene linear alkyl group, olefinmoiety moiety with along Z configuration with hydroxyl and group,two tert two-amide methoxy isomers. groups, Malyngamide an N-methyl was observed moiety, active presence in of chloromethylene moiety with Z configuration and two tert-amide isomers. Malyngamide was observed Mar. Drugs 2017, 15, 354 14 of 30

active in crustacean lethality test with a LD100 value of 33.30 mg/kg. Lipopeptide malyngamide Y(51) and a cyclic depsipeptide (+)-floridamide (52) were generated from Moorea producens from Florida [61]. A ketone group, amide group, ten methylene groups, two aliphatic methine groups, vinyl chloride atom, two methyl groups, and the methoxy group were observed by spectroscopicMar. Drugs analysis. 2017, 15,Malyngamide 354 Y (51) exhibited cytotoxic activity against human lung14 of 29 cancer cell −5 line (NCI-H460)crustacean and lethality mouse test with neuro-2a a LD100 neuroblastomavalue of 33.30 mg/kg. with Lipopeptide an EC50 malyngamidevalue of 1.45 Y (51×) and10 a µM/mL. Malyngamidecyclic 4depsipeptide (53), a new (+)-floridamide lipopeptide (52) were was generated isolated from from MooreaMoorea producensproducens from Florida, [61]. collected A from the Red Seaketone [62 group,]. Thisamide compoundgroup, ten methylene consisted groups of, two four aliphatic partial methine structures/fragments groups, vinyl chloride including atom, two methyl groups, and the methoxy group were observed by spectroscopic analysis. 7-methoxytetradec-4(E)-enoic acid (lyngbic acid), chloromethylene moiety along with two methylenes, Malyngamide Y (51) exhibited cytotoxic activity against human lung cancer cell line (NCI-H460) and olefinic methinemouse neuro-2a with amide neuroblastoma carbon andwith methoxyan EC50 value group, of 1.45 and × 10−N5 µM/mL.-substituted Malyngamide pyrrole-2-one 4 (53), a new substructure. Malyngamidelipopeptide 4 (53 )was exhibited isolated from activity Moorea against producens lung, collected carcinoma from the (A549), Red Sea colorectal [62]. This carcinomacompound (HT-29), consisted of four partial structures/fragments including 7-methoxytetradec-4(E)-enoic acid (lyngbic and breast adenocarcinoma (MDA-MB-231) with GI50 values of 40, 50, and 44 µM, respectively. acid), chloromethylene moiety along with two methylenes, olefinic methine with amide carbon and A linear lipopeptide, almiramide D (54), was isolated from the extract of Oscillatoria nigroviridis, methoxy group, and N-substituted pyrrole-2-one substructure. Malyngamide 4 (53) exhibited activity collected fromagainst thelung Caribbeancarcinoma (A549), Sea colorectal [63]. Five carcinoma amino (HT-29), acid and residues breast adenocarcinoma including alanine,(MDA-MB- isoleucine, methyl isoleucine231) with GI ester50 values and of 40, two 50, and methyl 44 µM,valine respectively. esters together with an additional acyl moiety identified as 2-methyl-oct-7-ynoicA linear lipopeptide, almiramide acid (Moya) D (54), was were isolated detected from the by extract spectroscopic of Oscillatoria analysis nigroviridis with, L form collected from the Caribbean Sea [63]. Five amino acid residues including alanine, isoleucine, methyl as absolute configuration. Almiramide D exhibited potent toxicity against (Artemia salina) nauplii isoleucine ester and two methyl valine esters together with an additional acyl moiety identified as 2- with an LCmethyl-oct-7-ynoic50 value of 3.5 µacidg/mL. (Moya) In were 2017, de atected new by anti-trypanosomal spectroscopic analysis lactam, with L form hoshinolactam as absolute (55) was isolated fromconfiguration. a marine Almiramide cyanobacterium D exhibited sp. potent collected toxicity against in Okinawa (Artemia salina [64].) nauplii Hoshinolactam with an LC50possessed four methylvalue groups, of 3.5 µg/mL. four In protons 2017, a new of anti-trypanosomal cyclopropane lactam, ring, twohoshinolactam olefinic ( protons55) was isolated and from two carbonyl a marine cyanobacterium sp. collected in Okinawa [64]. Hoshinolactam possessed four methyl groups. Additionally, the analysis suggested the presence of two fragments derived from groups, four protons of cyclopropane ring, two olefinic protons and two carbonyl groups. 4-hydroxy-5-isobutyl-3-methylpyrrolidin-2-oneAdditionally, the analysis suggested the presen (HIMP)ce of two andfragments 3-(2-propylcyclopropyl) derived from 4-hydroxy-5- acrylic acid (PCPA). Theisobutyl-3-methylpyrrolidin-2-one absolute configuration of (HIMP) HIMP and unit 3-(2-propylcyclopropyl) was determined to acrylic be 2R acid, 3R (PCPA)., 4S, while The 4S, 5S for PCPA unit.absolute Hoshinolactam configuration exhibitedof HIMP unit potent was determined anti-trypanosomal to be 2R, 3R, 4 activityS, while 4 againstS, 5S for PCPATrypanosoma unit. brucei Hoshinolactam exhibited potent anti-trypanosomal activity against Trypanosoma brucei with an IC50 with an ICvalue50 value of 3.9 of nM 3.9 (Figure nM (Figure11, Table 111). , Table1).

Figure 11. Chemical structures of: maylngamide (50); malyngamide Y (51); (+)-floridamide (52); Figure 11. Chemical structures of: maylngamide (50); malyngamide Y (51); (+)-floridamide (52); malyngamide 4 (53); almiramide D (54); and hoshinolactam (55). malyngamide 4 (53); almiramide D (54); and hoshinolactam (55).

Mar. Drugs 2017, 15, 354 15 of 30

Table 1. Bioactive secondary metabolites isolated from cyanobacteria in peptide class.

Compounds Species Bioactivity References Urumamide (1) Okeania sp. Anticancer [32] Medusamide A (2) Cyanobacterial sp. No cytotoxicity [33] Odoamide (3) Okeania sp. Brine shrimp toxicity [34] Bouillonamide (4) Moorea bouillonii Antitumor [35] Cyanobacterial Companeramides A–B (5–6) Antiplasmodium [36] assemblage Dudawalamides A–D (7–10) Moorea producens Antiplasmodium and Antiparasitic [37] Kohamamides A–C (11–13) Okeania sp. Weak against Cancer [38] Kohamamide B (12) Okeania sp. Potent cytotoxicity [38] Viequeamide A–B (14–15) Rivularia sp. Potent anticancer activity [39] Pitiprolamide (16) Lyngbya majuscula Weak cytotoxic activity [40] Pitipeptolide C–E (17–19) Lyngbya majuscula Weak cytotoxic activity [41] Pitipeptolide (F) (20) Lyngbya majuscula Potent microbial activity [41] Apratoxin H (21) Moorea producens Anticancer activity [42] Apratoxin A sulfoxide (22) Moorea producens No cytoxicity [42] Samoamide A (23) Symploca sp. Anticancer activity [43] Wewakzole B (24) Moorea producens Anticancer activity [44] Odobromoamide (25) Okeania sp. Antitumor activity [46] Anabaenopeptins NP 883, 869, 867, Cyanobacterial sp. No cytotoxicity [47] 865, 813 (26–30) Maedamide (31) Lyngbya sp. Strong anti-chymotrypsin [48] Caldoramide (32) Caldora penicillata Antitumor [49] Tasiamides C–E (33–35) Symploca sp. No cytotoxicity [50] Tesiamide F (36) Lyngbya sp. Anti-proteolytic activity [51] Balticidin A–D (37–40) Anabaena cylindrica Antifungal [52] Hassallidins C–D (41–42) Anabaena sp. Anti- fungal [53] Kurahyne (43) Lyngbya sp. Anti-cancer [55] Kurahyne B (44) Lyngbya sp. Anti-cancer [56] Jahanyne (45) Lyngbya sp. Anti-tumor activity [57] Kanamienamide (46) Moorea bouillonii Antitumor [58] inhibited sterol O-acyltransferase Biseokeaniamides A–C (47–49) Okeania sp. [59] SOAT1 and SOAT2 Maylngamide (50) Moorea producens Cytotoxic [60] Malyngamide Y, (+)-floridamide Moorea producens Anticancer [61] (51–52) Malyngamide 4 (53) Moorea producens Anticancer [62] Oscillatoria Almiramide D (54) Potent brine shirimp toxicity [63] nigroviridis Hoshinolactam (55) Cyanobacterial sp. Anti-trypanosomal activity [64]

2.2. Polyketides Trichophycin A (56), a vinyl chloride-containing linear polyketide, was generated from the crude extract of Trichodesmium thiebautii [65]. The latter consisted of three methyl groups, eleven methylenes, thirteen methines, and two quaternary carbon atoms with the presence of one aromatic ring. Trycophycin A showed several structural similarities to trichotoxin A and B [66] while possessing a longer polyketide chain than trichotoxin A with two additional alcohol groups and one additional branched methyl. Trichophycin A showed moderate cytotoxicity against neuro-2A cells and Mar. Drugs 2017, 15, 354 16 of 30

HCT-116 cells with EC50 values 6.5 ± 1.4 µM and 11.7 ± 0.6 µM, respectively. A hybrid tripeptide (peptide/polyketide) namely cryptomaldamide (57) was produced from Moorea producens [67]. Cryptomaldamide (57) consisted of four partial structures such as valine residue, unsaturated and methylated ketide-extended valine residue, serine group (hydroxy group), and CH3N2 (N methyl) group belonging to a guanidine carbon completing the fourth partial structure. The absolute configuration was established by Marfay’s method and determined to be L-configuration for N-methylvaline, valine and serine derivatives, while the vinyl methyl group with double bond was noted to be E configuration. Cryptomaldamide showed no activity against H-460 human lung cancer cells. Four unstaturated polyketide lactone derivatives, coibacins A–D (58–61) were isolated from Oscillatoria sp., Panama [68]. Spectroscopic analysis revealed the presence of α,β-unsaturated δ-lactone in all four compounds. The first two compounds (58 and 59) exhibited a methyl-substituted cyclo propyl ring, while the other two coibacin C and D (60 and 61) had methyl vinyl chloride moieties. Coibacin A (58) possessed two conjugated dienes separated by two methylene groups where the absolute configuration matched with S configuration of model α,β-unsaturated lactone ring while possessing a trans configured methyl cyclopropyl ring (S*, S*). Coibacin B (59) was found to be closely similar to coibacin A, excluding the two carbons which were absent in the dienes motif adjacent to the methyl cyclopropyl ring. Coibacin C (60) also contained similar feature as the above two compounds excluding the chlorine atom. Coibacin C possessed the same α,β-unsaturated δ-lactone with a difference observed in oxymethine, located adjacent to a methylene rather than an olefin, as well as two conjugated diene and a bis-allelic methylene connected with β-chloro and α-methyl substituents. Coibacin D (61) was similar to coibacin C (60), where coibacin D lack one of the two olefins forming the conjugated dienes in C (60). Moreover, the data analysis revealed the E-geometry of trisubstituted olefin in both C and D compounds. Coibacin A (58) showed potent activity against Leishmania donovani single amastigotes with an IC50 value of 2.4 µM. Coibacin D (61) exhibited potent cytotoxicity against NCI-H460 human lung cancer cells with an IC50 value of 11.4 µM, and coibacin B (59) exhibited anti-inflammatory activity in a cell based nitric oxide inhibition assay with an IC50 value of 5 µM (Figure 12, Table2).

Table 2. Bioactive secondary metabolites from cyanobacteria in polyketide class.

Compound Species Bioactivities References Trichophycin A (56) Trichodesmium thiebautii Anti-cancer [65] Cryptomaldamide (57) Moorea producens No Cytotoxicity [67] Coibacins A–D (58–61) Oscillatoria sp. Anti-parasite, cancer and inflammatory [68] Bastimolide A (62) Okeania hirsuta Antimalarial activity [69] Amentelides A–B (63–64) Gray cyanobacterium Anti-Cancer [70] Nuiapolide (65) Okeania plumata Anti-cancer [71] Anti-trypanasomal against Janadolide (66) Okeania sp. [72] Trypanosoma brucei brucei Polycavernoside D (67) Okeania sp. Anti-cancer [73] 3-methoxyaplysiatoxin and 3-methoxydebromoaplysiatoxin Trichodesmium erythraeum Anti-viral [74] (68–69) Mar. Drugs 2017, 15, 354 16 of 29

Oscillatoria sp., Panama [68]. Spectroscopic analysis revealed the presence of α,β-unsaturated δ- lactone in all four compounds. The first two compounds (58 and 59) exhibited a methyl-substituted cyclo propyl ring, while the other two coibacin C and D (60 and 61) had methyl vinyl chloride moieties. Coibacin A (58) possessed two conjugated dienes separated by two methylene groups where the absolute configuration matched with S configuration of model α,β-unsaturated lactone ring while possessing a trans configured methyl cyclopropyl ring (S*, S*). Coibacin B (59) was found to be closely similar to coibacin A, excluding the two carbons which were absent in the dienes motif adjacent to the methyl cyclopropyl ring. Coibacin C (60) also contained similar feature as the above two compounds excluding the chlorine atom. Coibacin C possessed the same α,β-unsaturated δ- lactone with a difference observed in oxymethine, located adjacent to a methylene rather than an olefin, as well as two conjugated diene and a bis-allelic methylene connected with β-chloro and α- methyl substituents. Coibacin D (61) was similar to coibacin C (60), where coibacin D lack one of the two olefins forming the conjugated dienes in C (60). Moreover, the data analysis revealed the E- geometry of trisubstituted olefin in both C and D compounds. Coibacin A (58) showed potent activity against Leishmania donovani single amastigotes with an IC50 value of 2.4 µM. Coibacin D (61) exhibited potent cytotoxicity against NCI-H460 human lung cancer cells with an IC50 value of 11.4 µM, and Mar.coibacin Drugs B2017 (59, 15) exhibited, 354 anti-inflammatory activity in a cell based nitric oxide inhibition assay17 with of 30 an IC50 value of 5 µM (Figure 12, Table 2).

Figure 12. 12. ChemicalChemical structures structures of: trichophycin of: trichophycin A (56); cryptomaldamide A (56); cryptomaldamide (57); and coibacins (57); and A–D coibacins (58–61). A–D (58–61). Table 2. Bioactive secondary metabolites from cyanobacteria in polyketide class.

A polyhydroxyCompound macrolide, bastimolideSpecies A (62) with a 40-membered Bioactivities ring was produced References from OkeaniaTrichophycin hirsuta, collectedA (56) fromTrichodesmium Panama thiebautii [69]. Bastimolide AAnti-cancer contained six partial structures [65] includingCryptomaldamide trisubstituted (57) α,β-unsaturatedMoorea producens lactone moiety, a tertNo-butyl Cytotoxicity group with (lactone methine,[67] Coibacins A–D (58–61) Oscillatoria sp. Anti-parasite, cancer and inflammatory [68] adjacentBastimolide three methylenes, A (62) and distalOkeania secondary hirsuta alcohol), 1,3,5-triolAntimalarial group activity and five 1,5-diol [69] group. TheAmentelides absolute configurations A–B (63–64) ofGray 1,5-diol cyanobacterium and 1,3,5-triol group were Anti-Cancer assigned as syn and [70]anti/syn , respectively.Nuiapolide Bastimolide (65) A exhibitedOkeania potential plumata antimalarial activityAnti-cancer against four resistant pathogens[71] Anti-trypanasomal against of PlasmodiumJanadolide falciparum (66) with IC50 valuesOkeania betweensp. 80 and 270 nM while exhibiting some toxicity[72] to Trypanosoma brucei brucei the control Vero cells with an IC50 value 2.1 µM. Polyhydroxylated 40 membered ring macrolactone, Polycavernoside D (67) Okeania sp. Anti-cancer [73] amentelides3-methoxyaplysiatoxin A (63) and and B ( 64 ) were produced from a gray cyanobacterium near Puntan dos Amantes, Tumon3-methoxydebromoaplysiatoxin Bay, Guam [70]. An αTrichodesmium,β-unsaturated erythraeum ester group, supportedAnti-viral by a carbonyl, methyl [74] and a vinyl group(68–69 was) noted. It was also confirmed that amentelides A and B comprised of a tert-butyl moiety, hence proving a one ring system with Z configuration. Amentelide B (64) was a monoacetylated analog containing an additional acetyl group instead of a hydroxyl group on position C-33 compared to amentelide A (63). Amentelide A exhibited potent antiproliferative activity in HT29 colorectal adenocarcinoma with an IC50 value of 0.87 ± 0.02 and HeLa cervical carcinoma cells with an IC50 value of 0.87 ± 0.07. Amentelide B (64) showed antiproliferative activity in HT29 colorectal adenocarcinoma with IC50 12 ± 1.6 and HeLa cervical carcinoma cells with IC50 9.9 ± 0.05. Another polyhydroxylated macrolactone, nuiapolide (65) was generated from Okeania plumata, near Lehua Rock [71]. The presence of an alkene or α,β-unsaturated ester group supported by carbonyl, methyl and a vinyl group as well as the presence of a tert-butyl group, and nine hydroxyl groups distributed throughout the saturated hydrocarbon ring structure was proved by spectroscopic analysis. Nuiapolide exhibited anti-chemotactive activity at concentrations as low as 1 µg/mL (1.3 µM) against Jurkat cells (human cancerous T lymphocyte cell line). A new cyclic polyketide-peptide hybrid namely Janadolide (66), was isolated from Okeania sp. collected near Janado, Okinawa [72]. Janadolide (66) consisted of two methyl groups, a tert-butyl group, vinyl methyl group, olefinic proton, six carbonyl groups and one double bond. Moreover, five amino acid units and one hydroxy unit like N-Me-Leu, N-Me-Ala, Gly, Val, Pro, and the presence of a residue derived from polyketide moiety (7-hydroxy-2,5,8,8-tetramethylnon-5-enoic) acid were noted. The olefinic bond in the polyketide moiety was established to be E configuration, and all amino acid residues were set to be L-configuration. Janadolide exhibited potent antitrypanasomal activity against Trypanosoma bruceibrucei with an IC50 Mar. Drugs 2017, 15, 354 18 of 30

value of 47 nM, which was stronger than the commonly used therapeutic drug, suramin (IC50 value of 1.2 µM). Jandolide showed no cytotoxicity against human cells. A unique class of marine-derived 16 membered macrolide, polycavernoside D (67) was isolated from a red colored cyanobacterial Okeania sp. [73]. Polycavernoside D consisted of an allylic conjugated decanol triene, methylene with hydroxyl-methine, two terminal oxygenated methine, and two pentose pyranose rings with additional presence of two gem-dimethyl groups, ester linkage, the tetrahydropyran ring, tetrahydrofuran ring and α-hemiketal ketone group. Polycavernoside D exhibited moderate activity against H-460 human lung cancer cells with an EC50 value of 2.5 µM. In 2014, two new polyketides, 3-methoxyaplysiatoxin (68) and 3-methoxydebromoaplysiatoxin (69), analogs of aplysiatoxin, were produced from Trichodesmium erythraeum, from Singapore [74]. The absence of bromide ion found in 3-methoxydebromoaplysiatoxin (69) made it different from 3-methoxyaplysiatoxin (68). 3-methoxydebromoaplysiatoxin (69) showed significant activity against chikungunya virus in post-treatment of infected SJCRH30 cells with an EC50 value of 2.7 µM (FigureMar. Drugs 13 2017 and, 15 Table, 354 2). 18 of 29

Figure 13. 13. The Thechemical chemical structures structures of: bastimolide of: bastimolide A (62); amentelides A (62 );A ( amentelides63) and B (64); Anuiapolide (63) and (65 B); (janadolide64); nuiapolide (66); polycavernoside (65); janadolide D (67); ( 663-methoxyaplysiatoxin); polycavernoside (68 D); (and67); 3-methoxydebromoaplysiatoxin 3-methoxyaplysiatoxin (68); and(69). 3-methoxydebromoaplysiatoxin (69).

2.3. Alkaloids Alkaloids are a chemically diverse group of naturally nitrogen-containing compounds that are produced by a large variety of marine microorganisms. Many alkaloids are pharmacologically well characterized and are mainly used as clinical remedies, ranging from chemotherapeutics to analgesic agents. Compared to all different types of natural compounds, alkaloids are identified by an enormous structural diversity with no uniform distribution. These marine alkaloids are frequently produced as potent toxins against predators. As such, more than thousands of alkaloids have been isolated from cyanobacteria. A new hybrid thiazoline-containing alkaloid, laucysteinamide A (70), which was a monomeric analog of a disulfide-bonded dimeric compound, somocystinamide A was isolated from Caldora penicillata, collected at Lau Lau Bay Saipan, Northern Mariana Island [75]. The presence of an amide N-methyl group, a linear alkyl chain of eight sp2 carbons forming one mono-substituted vinylidene moiety, two di-substituted trans alkenes and an imine functional group with methyl thiazoline ring were revealed by spectroscopic techniques with the absolute configuration assigned as 2R. This compound was mildly cytotoxic to H-460 human non-small cell lung cancer cells with an IC50 value of 11 µM. Carriebowlinol [5-hydroxy-4-(chloromethyl)-5,6,7,8-tetrahydroquinoline] (71),was isolated from a non-polar extract of an abundant cyanobacterial mat collected on the coral reef at Carrie Bow

Mar. Drugs 2017, 15, 354 19 of 30

2.3. Alkaloids Alkaloids are a chemically diverse group of naturally nitrogen-containing compounds that are produced by a large variety of marine microorganisms. Many alkaloids are pharmacologically well characterized and are mainly used as clinical remedies, ranging from chemotherapeutics to analgesic agents. Compared to all different types of natural compounds, alkaloids are identified by an enormous structural diversity with no uniform distribution. These marine alkaloids are frequently produced as potent toxins against predators. As such, more than thousands of alkaloids have been isolated from cyanobacteria. A new hybrid thiazoline-containing alkaloid, laucysteinamide A (70), which was a monomeric analog of a disulfide-bonded dimeric compound, somocystinamide A was isolated from Caldora penicillata, collected at Lau Lau Bay Saipan, Northern Mariana Island [75]. The presence of an amide N-methyl group, a linear alkyl chain of eight sp2 carbons forming one mono-substituted vinylidene moiety, two di-substituted trans alkenes and an imine functional group with methyl thiazoline ring were revealed by spectroscopic techniques with the absolute configuration assigned as 2R. This compound was mildly cytotoxic to H-460 human non-small cell lung cancer cells with an IC50 value of 11 µM. Carriebowlinol [5-hydroxy-4-(chloromethyl)-5,6,7,8-tetrahydroquinoline] (71),was isolated from a non-polar extract of an abundant cyanobacterial mat collected on the coral reef at Carrie Bow Cay, Belize [76]. Analysis revealed the presence of one trisubstituted pyridine ring, a chloromethyl moiety (ClCH2), benzylic like secondary hydroxyl group, and the hydroxy methine connected to three methylene group (-CHOH-CH2-CH2-CH2-moeity) followed by the absolute configuration being (+)-5(S)-hydroxy-4-(chloromethyl)-5,6,7,8-tetrahydroquinoline. Carriebowlinol exhibited strong anti-fungal activity against Dendryphiella salina, Lindra thalassiae, and Fusarium sp. with IC50 values of 0.5 µM, 0.4 µM, and 0.2 µM, respectively. This compound also exhibited potent anti-bacterial activity against Vibrio sp. Four nitrile-containing fischerindole-type alkaloids, 12-epi-fischerindole I (72) and deschloro 12-epi-fischerindole I nitrile (73), 12-epi-fischerindole W (74) and deschloro 12-epi-fischerindole W nitrile (75) were obtained from the extract of Fischerella sp. [77]. 1,2 disubstituted indole moiety, a vinyl group with a terminal (E and Z isomers), three methyl groups, isonitrile unit, tetrasubstituted double bond and an isolated spin system consisting of two methines while connected by a methylene (CHCH2CH) from C-13 to C-15 were present in the structure (72). The relative absolute configuration was determined as 12R*, 13R*, and 15R*. The spectral data of deschloro 12-epi-fischerindole I nitrile (73) showed the absence of a chlorine atom, as well as a methine signal at C-15, was replaced by a methylene to form a spin system as CHCH2CH2 with the relative configuration being 12R* and 15R*. 12-epi-fischerindole W nitrile (74) possessed a six membered ring, which was not observed in all previously known fishcerindoles indicating that the sequence of the spin system was shortened comparatively to (72) and (73). The absolute configuration was established as 11R*, 12R*, and 13R*. Finally, deschloro 12-epi-fischerindole W nitrile (75) showed close similarity to (68) (3-methoxyaplysiatoxin) excluding the absence of chlorine atom. On the other hand, the difference observed at H-13 to H-14 (CH2CH2), indicated that the methine at H-13 in (74) was replaced by methylene in (75). The stereochemistry was noted to be 11R*, and 12R*. Deschloro 12-epi-fischerindole I nitrile (73) showed weak cytotoxic activity against HT-29 cells with an IC50 value of 23 µM (Figure 14, Table3). Mar. Drugs 2017, 15, 354 20 of 30 Mar. Drugs 2017, 15, 354 20 of 29

FigureFigure 14. Chemical 14. Chemical structures structures of: of: laucysteinamide laucysteinamide A A (70 (70); );carriebowlinol carriebowlinol (71); ( 7112-epi-fischerindole); 12-epi-fischerindole I (72) and deschloro 12-epi-fischerindole I nitrile (73); 12-epi-fischerindole W (74); and deschloro 12- I(72) and deschloro 12-epi-fischerindole I nitrile (73); 12-epi-fischerindole W (74); and deschloro epi-fischerindole W nitrile (75). 12-epi-fischerindole W nitrile (75). Three hapalindole-type alkaloids, namely hapalindole X (76), deschloro hapalindole I (77), and 13-hydroxyTable dechlorofontonamide 3. Bioactive secondary (78), metabolites were isolated from cyanobacteria from the inextract alkaloid of class.two cultured cyanobacterium species; Westiellopsis sp. and Fischerella muscicola [78]. Spectral analysis of hapalindoleCompounds X (76) confirmed the presence Speciesof an exomethylene moiety, Bioactivities a vinyl group and a terminal References (E, Z Laucysteinamideisomers) including A (70 )gem-dimethylCaldora groups Penicillata which together formedAnticancer a seven-carbon spin system [75] bearingCarriebowlinol configuration (71 10)S*, 11R*, 13R*, Cyanobacterial and 15R*. Deschloro mat hapalindole Anti-fungal I (77) was a derivative of [76 the] known12-epi-fischerindole hapalindole I and I (72 )found to be closelyFischerella similarsp. to hapalindole X. No The cytotoxicity presence of a vinyl group [77] withDeschloro terminal 12-epi-fischerindole E and Z isomers I (73) at the positionFischerella ofsp. C-12 instead of exomethylene Anti-cancer moiety proved [77 the] difference12-epi-fischerindole from other W hapalindoles. (74) TheFischerella relativesp. configuration was No established cytotoxicity to be 12R*, 15 [77S]*. DeschloroFinally, the 12-epi-fischerindole analysis revealed W ( 75that) 13-hydroxyFischerella dechlorofontonamidesp. No(78 cytotoxicity) was the hydroxyl derivative [77] of previously known alkaloid structure dechlorofontonamide with the configuration being 12R*, hapalindole X (76) Westiellopsis sp. Anti-cancer and anti-microbial [78] 13S*, 15S*. Hapalindole X showed moderate cytotoxicity against HT-29 (colon), MCF-7 (breast), NCI- deschloro hapalindole I (77) Fischerella muscicola Anti-cancer and anti-microbial [78] H460 (lung) and SF268 (CNS) cancer cells with IC50 values of 24.8, 35.4 ± 2.8, 23 ± 4.6, 23.5 ± 9.5µM, Westiellopsis sp. and 13-hydroxydechlorofontonamiderespectively. It also exhibited (78 antimicrobial) activity against MycobacteriumAnti-cancer and anti-microbialtuberculosis and Candida [78] Fischerella muscicola albicans with an IC50 value of 2.5 µM and moderate cytotoxicity in the Vero cell assay with an IC50 fischambiguines A–B (79–80), Fischerella ambigua. Anti-tuberculosis [79] Ambiguinevalue of P35.2 (81) µM. and Ambiguine Q (82) Four hapalindole type alkaloids, namely fischambiguines A (79) and B (80), ambiguine P (81) and ambiguine Q nitrile (82), were produced from Fischerella ambigua [79]. Fischambiguines A (79) Threewas confirmed hapalindole-type to have 1,2,3-trisubstituted alkaloids, namely aromatic hapalindole moiety, an exomethylene X (76), deschloro moiety, hapalindole a vinyl group I (77), andand 13-hydroxy a terminal dechlorofontonamide(E, Z isomers) including five (78 ),methyl were groups isolated and an from isolated the spin extract system of CH two2CH2 culturedCH cyanobacteriumfrom C-13 to C-15 species; along Westiellopsiswith the presencesp. of an and isonitrileFischerella unit at muscicola C-11 and a[ 78hydroxyl]. Spectral group at analysis C-10. of hapalindoleThe configuration X (76) confirmed of fischambiguine the presence A (79 of) was an exomethylene10R*, 11R*, 12R moiety,*, and 15 aR*. vinyl Fischambiguine group and B a terminal(80) (E, Zshowedisomers) theincluding presence ofgem epoxy-dimethyl unit at C-25 groups and C- which26 instead together of an exomethylene formed a seven-carbon group and a chlorine spin system bearingsubstitution configuration at C-13 10comparedS*, 11R*, to 13 AR where*, and the 15 configurationR*. Deschloro was hapalindole assigned as 10 I (R77*,) 11 wasS*, 12 a derivativeR*, 13R*, of 15R* and 25R*. Ambiguine P (81) was an analog of ambiguine isonitriles where the noticed point was the known hapalindole I and found to be closely similar to hapalindole X. The presence of a vinyl the absence of isonitrile unit with the absolute configuration being 12R* and 15R*. Ambiguine Q group with terminal E and Z isomers at the position of C-12 instead of exomethylene moiety proved nitrile (82) showed the presence of an indole moiety, vinyl group and a terminal (E, Z isomers) the difference from other hapalindoles. The relative configuration was established to be 12R*, 15S*. including five methyl groups, tetrasubstituted double bond and an isolated spin system CH2CH2CH Finally, the analysis revealed that 13-hydroxy dechlorofontonamide (78) was the hydroxyl derivative of previously known alkaloid structure dechlorofontonamide with the configuration being 12R*, 13S*, 15S*. Hapalindole X showed moderate cytotoxicity against HT-29 (colon), MCF-7 (breast), NCI-H460 (lung) and SF268 (CNS) cancer cells with IC50 values of 24.8, 35.4 ± 2.8, 23 ± 4.6, 23.5 ± 9.5µM, Mar. Drugs 2017, 15, 354 21 of 30 respectively. It also exhibited antimicrobial activity against Mycobacterium tuberculosis and Candida albicans with an IC50 value of 2.5 µM and moderate cytotoxicity in the Vero cell assay with an IC50 value of 35.2 µM. Four hapalindole type alkaloids, namely fischambiguines A (79) and B (80), ambiguine P (81) and ambiguine Q nitrile (82), were produced from Fischerella ambigua [79]. Fischambiguines A (79) was confirmed to have 1,2,3-trisubstituted aromatic moiety, an exomethylene moiety, a vinyl group and a terminal (E, Z isomers) including five methyl groups and an isolated spin system CH2CH2CH from C-13 to C-15 along with the presence of an isonitrile unit at C-11 and a hydroxyl group at C-10. The configuration of fischambiguine A (79) was 10R*, 11R*, 12R*, and 15R*. Fischambiguine B (80) showed the presence of epoxy unit at C-25 and C-26 instead of an exomethylene group and a chlorine substitution at C-13 compared to A where the configuration was assigned as 10R*, 11S*, 12R*, 13R*, 15R* and 25R*. Ambiguine P (81) was an analog of ambiguine isonitriles where the noticed point was the absence of isonitrile unit with the absolute configuration being 12R* and 15R*. Ambiguine Q nitrile (82) showed the presence of an indole moiety, vinyl group and a terminal (E, Z isomers) including five methyl groups, tetrasubstituted double bond and an isolated spin system CH2CH2CH from C-13 to C-15 as well as isonitrile group. The configuration of ambiguine Q nitrile was seen as 12R* and 15R*. Mar. Drugs 2017, 15, 354 21 of 29 Fischambiguine A (79) exhibited antibiotic activities against Mycobacterium tuberculosis, Staphylococcus aureus, Escherichiafrom C-13 to coli C-15and as wellCandida as isonitrile albicans group.with The MICconfiguration values of of ambiguine >100 µ M,Q nitrile 82.3 wasµM, seen >100 as µM and 15.3 µM, respectively.12R* and 15R*. Fischambiguine Fischambiguine A B ( (7980) ),exhibited exhibited antibiotic activity activities against againstMycobacterium Mycobacterium tuberculosis, tuberculosis, Staphylococcus aureus, Escherichia coli and Candida albicans with MIC values of >100 µM, Bacillus anthracis Staphylococcus aureus Mycobacterium smegmatis Escherichia coli 82.3 µM,, >100 µM and 15.3 µM, ,respectively. Fischambiguine B, and(80), exhibited activity withagainst MIC values of 2.0, 28.7,Mycobacterium 19.4, 23.4, andtuberculos >100is, µBacillusM, respectively. anthracis, Staphylococcus It also showed aureus, inhibitoryMycobacterium cytotoxicity smegmatis, and against Vero cells withEscherichia an IC50 value coli with of MIC >128 valuesµM. of Ambiguine 2.0, 28.7, 19.4, P nitrile23.4, and (81 >100) revealed µM, respectively. antimicrobial It also showed activity against Mycobacteriuminhibitory tuberculosis cytotoxicity, Staphylococcus against Vero cells aureus with ,an and IC50Candida value of albicans>128 µM. withAmbiguine MIC valuesP nitrile of(81 >100,) >100 µrevealed antimicrobial activity against Mycobacterium tuberculosis, Staphylococcus aureus, and Candida and 32.9 albicansM, respectively with MIC values (Figure of >100, 15, >100 Table and3). 32.9 µM, respectively (Figure 15, Table 3).

Figure 15. Chemical structures of: hapalindole X (76); deschloro hapalindole I (77); and 13- Figure 15. Chemical structures of: hapalindole X (76); deschloro hapalindole I (77); hydroxydechlorofontonamide (78); fischambiguines A (79) and B (80); ambiguine P (81); and and 13-hydroxydechlorofontonamideambiguine Q (82) nitrile. (78); fischambiguines A (79) and B (80); ambiguine P (81); and ambiguine Q (82) nitrile. 2.4. Lipids 2.4. Lipids Fatty acid amides are one of the typical lipophilic class of compounds, which are highlighted by the presence of an amide bond in a fatty acid chain and in some cases with incorporated halogen Fattyatoms. acid amidesSince the arelast onetwo decades, of the typicalan assortment lipophilic of fatty class acid ofamides compounds, have been whichproduced are from highlighted by the presencemarine ofcyanobacteria an amide including bond in pitiamide a fatty acidA with chain their andanalogs in 1 someE-pitiamide cases B withand 1Z incorporated-pitiamide B, halogen atoms. Sinceserinolamide the last A, two propenediester, decades, an bartolosides, assortment columbamides of fatty acid A–C, amides kimbeamides, have been kalkitoxin, produced from taveuniamides, besarhanamides and credneramides. marine cyanobacteriaIn 2011, two including new endocannabinoid-like pitiamide A lipids, with namely their analogsserinolamide 1E -pitiamideA (83) and propenediester B and 1Z-pitiamide B, serinolamide(84), were A, identified propenediester, [80] and isolated bartolosides, from the extracts columbamides of Lyngbya majuscula A–C, kimbeamides,and Oscillatoria sp. kalkitoxin, taveuniamides,collected besarhanamides at Papua New Guinea and credneramides.and Panama, respectively. The structure of serinolamide A (83) showed the presence of three methyl groups, a monounsaturated alkyl chain, hydroxyl and amide- carbonyl groups as well as a 1st partial structure being saturated fatty acid moiety and a 2nd substructure consisting of a dimethyl serinol moiety, where the linkage in between oxygen-bonded methylenes with nitrogen group was observed. Analysis of propenediester (84) revealed the presence of two methyl groups at both ends, ethyl groups, two ester groups, and a saturated fatty acid chain with 16 methylenes. Both compounds (83) and (84) were evaluated for human cannabinoid receptors (G protein coupled-receptor) in radioligand binding assays. Serinolamide A (83) exhibited moderate affinity for the CB1 receptor with an IC50 value of 2.3 ± 0.1 µM, and found inactive for the CB2 receptor with an IC50 value of >10 µM. Two geometric isomers/analogs related to previously known pitiamide A, namely 1E-pitiamide B (85) and 1Z-pitiamide B (86), were isolated from marine cyanobacterium sp. in the Mariana Islands [81]. 1E-pitiamide B (85) contained a ketone group, an ester linkage, two

Mar. Drugs 2017, 15, 354 22 of 30

In 2011, two new endocannabinoid-like lipids, namely serinolamide A (83) and propenediester (84), were identified [80] and isolated from the extracts of Lyngbya majuscula and Oscillatoria sp. collected at Papua New Guinea and Panama, respectively. The structure of serinolamide A (83) showed the presence of three methyl groups, a monounsaturated alkyl chain, hydroxyl and amide-carbonyl groups as well as a 1st partial structure being saturated fatty acid moiety and a 2nd substructure consisting of a dimethyl serinol moiety, where the linkage in between oxygen-bonded methylenes with nitrogen group was observed. Analysis of propenediester (84) revealed the presence of two methyl groups at both ends, ethyl groups, two ester groups, and a saturated fatty acid chain with 16 methylenes. Both compounds (83) and (84) were evaluated for human cannabinoid receptors (G protein coupled-receptor) in radioligand binding assays. Serinolamide A (83) exhibited moderate affinity for the CB1 receptor with an IC50 value of 2.3 ± 0.1 µM, and found inactive for the CB2 receptor with an IC50 value of >10 µM. Two geometric isomers/analogs related to previously known pitiamide A, namely 1E-pitiamide B (85) and 1Z-pitiamide B (86), were isolated from marine cyanobacterium sp. in the Mariana Islands [81]. 1E-pitiamide B (85) contained a ketone group, an ester linkage, two methyl groups, a terminally chlorinated conjugated diene, and an isolated C–C double bond with threeMar. partialDrugs 2017 structures., 15, 354 However, the terminally chlorinated conjugated diene of22 compoundof 29 (86) observed as Z-E configuration differentiated it from that of (85). Both compounds (85) and (86) weremethyl evaluated groups, fora terminally their anti-proliferative chlorinated conjugated effects diene, against and an HCT116 isolated colorectalC–C double cancerbond with cells with three partial structures. However, the terminally chlorinated conjugated diene of compound (86) IC values of 5.1 µM and 4.5 µM, respectively. A new class of di- and tri-chlorinated acyl amides 50 observed as Z-E configuration differentiated it from that of (85). Both compounds (85) and (86) were cannabinomimeticevaluated for compoundstheir anti-proliferative namely effects columbamides against HCT116 A–C colorectal (87–89) cancer were producedcells with IC from50 values the of cultured extract of5.1 cyanobacterium µM and 4.5 µM, respectively. species [82 A]. new Columbamide class of di- and A tri-chlorinated (87) revealed acyl the amides presence cannabinomimetic of N-methyl amide adjacentcompounds to a carbonyl namely group, columbamidesO-methyl A–C group, (87– an89) acetoxywere produced group, andfrom anthe alkyl cultured chain extract as well of as two chlorinecyanobacterium atoms. Columbamide species [82]. BColumbamide (88) was an A analog(87) revealed of columbamide the presence of N A-methyl where amide the only adjacent difference observedto betweena carbonyl both group, was O-methyl the presence group, an of anacetoxy additional group, and chlorine an alkyl atom chain at as the well terminal as two chlorine C-16, which in atoms. Columbamide B (88) was an analog of columbamide A where the only difference observed gem 89 turn showedbetween a terminalboth was the presence-dichloro of an functionality. additional chlorine On the atom other at the hand, terminal columbamide C-16, which Cin (turn) lack an acetoxyshowed group a at terminal the C-20 gem position-dichloro comparedfunctionality. to On columbamide the other hand, A (columbamide87). The absolute C (89) lack configuration an of the dimethylatedacetoxy group at and the acetylatedC-20 position serinol compared residue to columbamide was established A (87). The by absolute Marfay’s configuration method, asof D- and L-N-methyl-the dimethylatedO-methylserinol. and acetylated Both compoundsserinol residue A was and established B exhibited by Marfay’s potent affinitymethod, foras D the- and CB L-1Nreceptor- methyl-O-methylserinol. Both compounds A and B exhibited potent affinity for the CB1 receptor as as well as for the CB2 receptor with IC50 values of 0.59 ± 0.08 µM, 0.41 ± 0.06 µM and 1.03 ± 0.12 µM, well as for the CB2 receptor with IC50 values of 0.59 ± 0.08 µM, 0.41 ± 0.06 µM and 1.03 ± 0.12 µM, 0.86 0.86 ± 0.09 µM, respectively (Figure 16, Table4). ± 0.09 µM, respectively (Figure 16, Table 4).

Figure 16. Chemical structures of: serinolamide A (83); propenediester (84); 1E-pitiamide B (85); 1Z- Figure 16. Chemical structures of: serinolamide A (83); propenediester (84); 1E-pitiamide B (85); pitiamide B (86); and columbamides A–C (87–89). 1Z-pitiamide B (86); and columbamides A–C (87–89). Table 4. Bioactive secondary metabolites from cyanobacteria in lipid class.

Compound Species Bioactivity References Serinolamide A (83) Lyngbia majuscula Moderate affinity for CB1 receptor [80] Propenediester (84) Oscillatoria sp. No affinity [80] 1E-pitiamide B (85) Cyanobacterial sp. Anti-cancer [81] 1Z-pitiamide B (86) Cyanobacterial sp. Anti-cancer [81] Columbamides A–C (87–89) Cyanobacterial sp. Potent affinity for CB1 and CB2 receptors [82] Nodosilinea sp. and Bartolosides A–D (90–93) Not reported [83] Synechocystis salina sp. Bartolosides E–K (94–100) Synechocystis Salina No cytotoxicity [84]

Four new glycosylated and halogenated dialkylresorcinol glycolipids, namely bartolosides A–D (90–93), were isolated from the crude extract of Nodosilinea sp. and Synechocystis salina sp. [83]. The presence of an aromatic/resorcinol ring, phenol group, glycosidic linkage (O-linkage), β-

Mar. Drugs 2017, 15, 354 23 of 30

Table 4. Bioactive secondary metabolites from cyanobacteria in lipid class.

Compound Species Bioactivity References

Serinolamide A (83) Lyngbia majuscula Moderate affinity for CB1 receptor [80] Propenediester (84) Oscillatoria sp. No affinity [80] 1E-pitiamide B (85) Cyanobacterial sp. Anti-cancer [81] 1Z-pitiamide B (86) Cyanobacterial sp. Anti-cancer [81]

Columbamides A–C (87–89) Cyanobacterial sp. Potent affinity for CB1 and CB2 receptors [82] Nodosilinea sp. and Bartolosides A–D (90–93) Not reported [83] Synechocystis salina sp. Bartolosides E–K (94–100) Synechocystis Salina No cytotoxicity [84]

Four new glycosylated and halogenated dialkylresorcinol glycolipids, namely bartolosides A–D (90–93), were isolated from the crude extract of Nodosilinea sp. and Synechocystis salina sp. [83]. The presence of an aromatic/resorcinol ring, phenol group, glycosidic linkage (O-linkage), β-xylopyranosyl moiety, two methyl groups, and two chlorinated alkyl chains with a propyl substituted at one end of the linear chain (CH2CH2CH3) was seen for bartoloside A (90). Bartoloside B (91) showed close similarity to bartoloside A (90) with a difference in the two sugar moieties including xylose and rhamnose. The absolute configuration of the sugar units was established as D-xylose and L-rhamnose. The difference observed in bartoloside C (92) was an absence of a substituted chlorine atom at CH-17 in the alkyl chain, while bartoloside D (93) bear an additionally substituted chlorine atom in the aromatic ring as compared to bartoloside B (91). Seven new glycolipids analog of bartoloside A, namely bartolosides E–K (94–100) were isolated from Synechocystis salina strain LEGE 060099, collected in Northern Portugal [84]. Spectroscopic data of bartolosides E–K (94–100) revealed that most of the regions were found highly similar to bartoloside A with different alkyl chain lengths or halogenation patterns. Bartoloside A (90) and E–K (94–100) showed cytotoxic activities against human cancer cell lines including bone osteosarcoma (MG-63), colon carcinoma (RKO), and mammary gland ductal carcinoma (T-47D) with an IC50 value of >10 µM. Moreover, bartoloside A and E were active against MG-63 cells, RKO cells, and T-47D with IC50 values of 22 and 39 µM, 40 and 40 µM, and 23 and 22 µM, respectively (Figure 17, Table4). Mar. Drugs 2017, 15, 354 23 of 29 xylopyranosyl moiety, two methyl groups, and two chlorinated alkyl chains with a propyl substituted at one end of the linear chain (CH2CH2CH3) was seen for bartoloside A (90). Bartoloside B (91) showed close similarity to bartoloside A (90) with a difference in the two sugar moieties including xylose and rhamnose. The absolute configuration of the sugar units was established as D- xylose and L-rhamnose. The difference observed in bartoloside C (92) was an absence of a substituted chlorine atom at CH-17 in the alkyl chain, while bartoloside D (93) bear an additionally substituted chlorine atom in the aromatic ring as compared to bartoloside B (91). Seven new glycolipids analog of bartoloside A, namely bartolosides E–K (94–100) were isolated from Synechocystis salina strain LEGE 060099, collected in Northern Portugal [84]. Spectroscopic data of bartolosides E–K (94–100) revealed that most of the regions were found highly similar to bartoloside A with different alkyl chain lengths or halogenation patterns. Bartoloside A (90) and E–K (94–100) showed cytotoxic activities against human cancer cell lines including bone osteosarcoma (MG-63), colon carcinoma (RKO), and mammary gland ductal carcinoma (T-47D) with an IC50 value of >10 µM. Moreover, bartoloside A and E were active against MG-63 cells, RKO cells, and T-47D with IC50 values of 22 and 39 µM, 40 Mar. Drugs 2017, 15, 354 24 of 30 and 40 µM, and 23 and 22 µM, respectively (Figure 17, Table 4).

Figure 17. Chemical structures of: bartolosides A–D ( 90–93); and bartolosides E–K (94–100).

3. Applications Cyanobacteria have been recognized as a productive source of secondary metabolites with possible biotechnological applications in the pharmacological area. Recently, production of natural products with commercial and medical applications has also heightened interest in investigating these organisms [20,85]. In fact, cyanobacteria have the ability to simultaneously produce potent toxins as well as infinite metabolites that have been praised for their antibacterial, antifungal, immunosuppressive, anticancer and anti-tuberculosis activities [86]. Associated secondary metabolites are from all classes including peptides, polyketides, alkaloids, terpenoids, and lipids. For example, tesiamide A and B exhibited cytotoxic activity against human nasopharyngeal carcinoma cell lines because of the presence of unique amino acid residue, 4-amino-3-hydroxy-5-phenylpentanoic acid and their chemically related analogs exhibited inhibitory activities against human nasopharyngeal carcinoma and non-small cell lung tumor cell lines [87–89]. Gamma linolenic acid (GLA), an important fatty acid in the human body, is converted into arachidonic acid and then into prostaglandin E2, involved in lowering blood pressure which is also important in lipid metabolism [90]. Prominently, brentuximab vedotin (trade name Adcetris), marine peptide-derived medicine, was approved by Mar. Drugs 2017, 15, 354 25 of 30 the U.S. Food Drug Administration (FDA) for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma [31]. It was also observed that cryptophycins, from Nostoc sp., were thousand times more potent than the current anticancer medications. Moreover, dolastatin 10 and its chemically associated analog, symplostatin, were potent microtubule polymerization inhibitors that had the ability to inhibit cancer growth [90,91]. Likewise, dolastatin 15, another member of dolastatin family, served as a weak tubulin inhibitor by adhering to the vinca region of tubulin and induced apoptosis through Bcl-2 phosphorylation in several malignant cell types. However, no clinical trial has been initiated with this compound because of its structural complexity, little synthetic yield, and poor water solubility [91]. An individual family of indole monoterpene alkaloids, namely welwitindolinones B and C, originally produced by true-branching heterocystous filamentous cyanobacterium Hapalosiphon welwitschii, were noted as potent antitumor agents that exhibited anti-mitotic activity with multidrug resistance (MDR) reversal properties [92]. Pitiamide A and its two analogs showed an anti-proliferative effect on HCT116 cells. Pitiamide A was tested individually and caused membrane hyperpolarization and the increase of intracellular calcium in HCT116. Specific cannabinoid receptors (CB1 and CB2) in central and peripheral mammalian tissues had been discovered due to an important development in neuropharmacological research [93,94]. Only few cannabinoids related medicinal products are available on the market and, as such, Sativex was introduced as the first medicine in this type of class [95]. Moreover, the National Cancer Institute had declared that a fat solvable photosynthetic pigment, β-carotene was anti-carcinogenic in nature. Eventually, it is beneficial to decrease the risk of heart infections by regulating the cholesterol level.

4. Conclusions This review presented a survey of the wide variety of recently published secondary metabolites from marine cyanobacteria highlighting peptides, polyketide, alkaloid, lipid parts and any combination thereof. Approximately 100 marine cyanobacterial metabolites were explained here with some focus on multiple attractive structural characteristics including amino acid residues, terminal fatty acyl residues (Dhoya, Hmoya, Amoya, etc.) and heterocyclic aromatic moieties such as thiazoline, chlorinated or dechlorinated alkyl linear chains and resorcinol rings. These underlined different features created not only structural diversity but also contributed significantly to the biological activities. Nevertheless, some of these metabolites were not of interest due to their weak bioactivities, but most of them displayed significant biological properties such as anticancer, antitumor, antimalarial, antifungal, antibacterial, and anti-inflammatory. The recently reported compounds with potent activities were: wewakzole B, kohamamide, samoamide, odobromoamide, uramamide, caldoramide, janadolide, laucysteinamide, trichophycin A and dudawalamides. Moreover, carriebowlinol, balticidins, and glycosylated hassallidins were found to be active against pathogenic fungi, which fascinated researchers in the pharmaceutical area due to a rise in the percentage of invading fungal infections and resistance to several currently accepted drugs. It was also observed that cyanobacteria could be easily cultured but complications arose during the isolation and elucidation processes of compounds due to the presence of partial structures to establish complex structures. As a whole, with the combination of knowledge from various fields, natural products from marine cyanobacteria should be regarded as a prolific source for biotechnological development and applications for pharmaceutical purposes.

Acknowledgments: This research work was financially supported by the Natural Science Foundation of China (Nos. 81573306 and 81520108028), SCTSM Project (No. 15431901000), and the SKLDR/SIMM Projects (SIMM 1705ZZ-01). The authors also thank NSF of Zhejiang (LY15C200004). Conflicts of Interest: The authors declare no conflict of interest. Mar. Drugs 2017, 15, 354 26 of 30

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