nutrients

Review Recent Advances in Phytochemistry and Biological Activity: A Comprehensive Review

Abdelsamed I. Elshamy 1,2 , Tarik A. Mohamed 3, Ahmed F. Essa 2, Ahmed M. Abd-El Gawad 4,5 , Ali S. Alqahtani 6,* , Abdelaaty A. Shahat 3,6 , Tatsuro Yoneyama 1, Abdel Razik H. Farrag 7, Masaaki Noji 1, Hesham R. El-Seedi 8,9,10 , Akemi Umeyama 1 , Paul W. Paré 11 and Mohamed-Elamir F. Hegazy 3,12,*

1 Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan; [email protected] (A.I.E.); [email protected] (T.Y.); [email protected] (M.N.); [email protected] (A.U.) 2 Chemistry of Natural Compounds Department, National Research Centre, 33 El Bohouth St., Dokki, Giza 12622, Egypt; [email protected] 3 Chemistry of Medicinal Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt; [email protected] (T.A.M.); [email protected] (A.A.S.) 4 Department of Botany, Faculty of Science, Mansoura University, Mansoura 35516, Egypt; [email protected] 5 Production Department, College of Food & Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia 6 Pharmacognosy Department, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia 7 Pathology Department; National Research Centre, Dokki, Giza 12622, Egypt; [email protected] 8 Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75 123 Uppsala, Sweden; [email protected] 9 Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Kom 32512, Egypt 10 College of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, 11 Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX 79409, USA; [email protected] 12 Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany * Correspondence: [email protected] (A.S.A.); [email protected] (M.-E.F.H.); Tel.: +966-114677246 (A.S.A.); +49-6131-3925751 (M.-E.F.H.)  Received: 12 September 2019; Accepted: 1 October 2019; Published: 7 October 2019 

Abstract: Background: Plants belonging to the genus Kaempferia (family: ) are distributed in Asia, especially in the southeast region, and Thailand. They have been widely used in traditional medicines to cure metabolic disorders, inflammation, urinary tract infections, fevers, coughs, hypertension, erectile dysfunction, abdominal and gastrointestinal ailments, asthma, wounds, rheumatism, epilepsy, and skin diseases. Objective: Herein, we reported a comprehensive review, including the traditional applications, biological and pharmacological advances, and phytochemical constituents of Kaempheria species from 1972 up to early 2019. Materials and methods: All the information and reported studies concerning Kaempheria plants were summarized from library and digital databases (e.g., Google Scholar, Sci-finder, PubMed, Springer, Elsevier, MDPI, Web of Science, etc.). The correlation between the Kaempheria species was evaluated via principal component analysis (PCA) and agglomerative hierarchical clustering (AHC), based on the main chemical classes of compounds. Results: Approximately 141 chemical constituents have been isolated and reported from Kaempferia species, such as isopimarane, abietane, labdane and clerodane diterpenoids, flavonoids, phenolic acids, phenyl-heptanoids, curcuminoids, tetrahydropyrano-phenolic, and steroids. A probable biosynthesis pathway for the isopimaradiene skeleton is illustrated. In addition, 15 main documented components of volatile oils of Kaempheria

Nutrients 2019, 11, 2396; doi:10.3390/nu11102396 www.mdpi.com/journal/nutrients Nutrients 2019, 11, 2396 2 of 33

were summarized. Biological activities including anticancer, anti-inflammatory, antimicrobial, anticholinesterase, antioxidant, anti-obesity-induced dermatopathy, wound healing, neuroprotective, anti-allergenic, and anti-nociceptive were demonstrated. Conclusions: Up to date, significant advances in phytochemical and pharmacological studies of different Kaempheria species have been witnessed. So, the traditional uses of these plants have been clarified via modern in vitro and Nutrients 2019, 11, 2396 2 of 38 in vivo biological studies. In addition, these traditional uses and reported biological results could be correlated viaillustrated.the chemical In addition, characterization 15 main docume ofnted these components plants. of All volatile these oils data of willKaempheria support were the biologists summarized. Biological activities including anticancer, anti-inflammatory, antimicrobial, in the elucidationanticholinesterase, of the biological antioxidant, mechanisms anti-obesity-induced of these plants.dermatopathy, wound healing, neuroprotective, anti-allergenic, and anti-nociceptive were demonstrated. Conclusions: Up to date, Keywords: significantKaempferia advances; traditional in phytochemical medicine; and pharmacological diterpenoids; studies flavonoids; of different phenolic; Kaempheria biosynthesis species have been witnessed. So, the traditional uses of these plants have been clarified via modern in vitro and in vivo biological studies. In addition, these traditional uses and reported biological results could be correlated via the chemical characterization of these plants. All these data will support the biologists in the elucidation of the biological mechanisms of these plants. 1. Introduction Keywords: Kaempferia; traditional medicine; diterpenoids; flavonoids; phenolic; biosynthesis From the first known civilization, medicinal plants have met primary care and health needs around the world [1–3]. Natural products, derived from plants, have enriched the pharmaceutical industry since time immemorial.1. Introduction So far, people of the developing countries depend upon the traditional medicines to cure daily alimentsFrom the first [4]. known The medicinalcivilization, medicinal plants areplants characterized have met primary by care a diversityand health needs of chemical and pharmacologicalaround constituents, the world [1–3]. owingNatural toproducts, their complicityderived from plants, and the have abundance enriched the ofpharmaceutical secondary metabolites. There are severalindustry factors since time that immemorial. causedthe So far, variations people of ofthe the developing secondary countries metabolites depend upon such the as ecological traditional medicines to cure daily aliments [4]. The medicinal plants are characterized by a diversity zones, weather,of chemical climates, and andpharmacological other natural constituents, factors owingvia theto their effects complicity on the and biosynthetic the abundance pathways of [1–3]. Zingiberaceaesecondary (the metabolites. ginger There family) are isseveral distributed factors that worldwide caused the comprising variations of 52thegenera secondary and more than 1300 plant speciesmetabolites [5, 6such]. Kaempferia as ecological iszones, a diverse weather, familyclimates, withand other members natural factors distributed via the effects widely on throughout the biosynthetic pathways [1–3]. Southeast AsiaZingiberaceae and Thailand, (the ginger including family) is somedistribute 60d speciesworldwide [ comprising5]. Several 52 generaKaempferia and morespecies than are used widely in folk1300 medicine, plant species including [5,6]. KaempferiaK. parviflora is a diverse, K. family pulchra with ,members and K. distributed galanga, (Figurewidely throughout1). In Laos and Thai, traditional medicinesSoutheast Asia derived and Thailand, from K. includ parvifloraing somerhizomes 60 species are [5]. reported Several Kaempferia for the treatmentspecies are used of inflammation, widely in folk medicine, including K. parviflora, K. pulchra, and K. galanga, (Figure 1). In Laos and Thai, hypertension,traditional erectile medicines dysfunction, derived abdominal from K. parviflora ailments rhizomes [6,7], andare reported improvement for the oftreatment the vitality of and blood flow [8]. Japaneseinflammation, use the hypertension, extract of erectileK. parviflora dysfunction,as a abdominal food supplement ailments [6,7], and and for improvement the treatment of the of metabolic disorders [9vitality]. K. pulchraand bloodis flow used [8]. Japanese extensively use the as extract a carminative, of K. parviflora as diuretic, a food supplement deodorant, and for and the euglycemic, treatment of metabolic disorders [9]. K. pulchra is used extensively as a carminative, diuretic, as well as fordeodorant, the treatment and euglycemic, of urinary as well tract as for infections, the treatment fevers, of urinary and tract coughs infections, [4]. fevers, The and rhizomes coughs of K. galanga are used as an[4]. anti-tussive,The rhizomes of expectorant,K. galanga are used anti-pyretic, as an anti-tussive, diuretic, expectorant, anabolic, anti-pyretic, and diuretic, carminative, anabolic, as well as for the curing ofand gastrointestinal carminative, as well ailments, as for the curing asthma, of gastrointestinal wounds, rheumatism, ailments, asthma, epilepsy, wounds, rheumatism, and skin diseases [10]. epilepsy, and skin diseases [10].

Figure 1. Traditional medicinal used Kaempheria species.

Extracts and purified compounds from select Kaempferia species are used for the treatment of knee osteoarthritis and the inhibition of a breast cancer resistance protein (BCRP), anti-inflammatory, anti-acne, anticholinesterase, anti-obesity-induced dermatopathy, wound healing, anti-drug resistant strains of Mycobacterium tuberculosis, neuroprotective, anti-nociceptive, human immunodeficiency Nutrients 2019, 11, 2396 3 of 33 virus type-1 (HIV-1) inhibitory activity, in vitro anti-allergenic, and larvicidal activity against Aedes aegypti [4,6–11]. The scientific literature such as, Google Scholar, Scifinder, PubMed, Springer, Elsevier, Wiley, Web of Science, were screened in the period between 1972–2019 in order to collect the up-to-date information of the traditional uses/applications, biological studies, and chemical characterization of Kaempheria species. All these collected data were addressed and summarized in our review article to highlight the potential ethnopharmacological importance of these plants.

2. Materials and Methods The scientific literature such as Google Scholar, Scifinder, PubMed, Springer, Elsevier, Wiley, Web of Science, etc., including all the traditional uses/applications, biological studies, and chemical characterization of Kaempheria species were collected between 1972–2019. All these collected data were adjusted and summarized in our review article due to the potential ethnopharmacological importance of these plants. The correlation between the Kaempheria species was evaluated based on the main chemical classes of compounds. The data matrix of seven Kaempferia species (K. angustifolia, K. elegans, K. galanga, K. marginata, K. parviflora, K. pulchra, and K. roscoeana) and six chemical classes (abietanes, labdanes and clerodanes, flavonoids, phenolic compounds, and chalcones) were subjected to principal component analysis (PCA) to identify correlation between different Kaempferia species. In addition, the similarity based on the Pearson correlation coefficient was determined via subjecting the dataset to an agglomerative hierarchical cluster (AHC). The PCA and AHC were performed using an XLSTAT statistical computer software package (version 2018, Addinsoft, NY, USA, www.xlstat.com).

3. Distribution Zingiberaceae (the ginger family) comprises 52 genera and more than 1300 plant species. Kaempferia is distributed worldwide with diverse members occurring throughout southeast tropical Asian countries such as Indonesia, , , Myanmar, Cambodia, and China, as well as Thailand, including some 60 species [5]. K. pulchra is a perennial herbal plant and widely cultivated in numerous tropical countries, involving Indonesia, Malaysia, Myanmar, and Thailand [12].

4. Traditional Uses Several Kaempferia species are used widely in folk medicine, including K. parviflora, K. pulchra, and K. galanga (Figure1). In Laos and Thai, traditional medicines derived from K. parviflora rhizomes are reported for the treatment of inflammation, hypertension, erectile dysfunction, abdominal ailments [6,7], and improvement of the vitality and blood flow [8]. Japanese folk medicine documented a positive effect of K. parviflora extract when used as a food supplement and for the treatment of metabolic disorders [9]. K. pulchra is used extensively as a carminative, diuretic, deodorant, and euglycemic, as well as for the treatment of urinary tract infections, fevers, and coughs [4]. K. galanga is sold as an industrial crop in the market, and its rhizome has been used as a flavor spice of various cooking [13]. The rhizomes of K. galanga is used as an anti-tussive, expectorant, anti-pyretic, diuretic, anabolic, carminative, as well as for curing of gastrointestinal ailments, asthma, wounds, rheumatism, epilepsy, and skin diseases [10]. In Malaysian folk medicines, several gingers belonging to the Zingiberaceae family especially, Kaempheria genus, are used in the treatment of several diseases such as stomach ailments, vomiting, cough, bruises, epilepsy, nausea, rheumatism, sore throat, wounds, eyewash, sore eyes, childbirth, liver complaints, muscular pains, ringworm, asthma, fever, malignancies, swelling, and several other disorders [14].

5. Biological Activity Extracts and purified compounds of Kaempferia species are used for the treatment of knee osteoarthritis and the inhibition of a breast cancer resistance protein (BCRP), anti-inflammatory, anti-acne, anticholinesterase, anti-obesity-induced dermatopathy, wound healing, anti-drug resistant Nutrients 2019, 11, 2396 4 of 38

5. Biological Activity Nutrients 2019Extracts, 11, 2396 and purified compounds of Kaempferia species are used for the treatment of knee4 of 33 osteoarthritis and the inhibition of a breast cancer resistance protein (BCRP), anti-inflammatory, anti- acne, anticholinesterase, anti-obesity-induced dermatopathy, wound healing, anti-drug resistant strains of Mycobacterium tuberculosis, neuroprotective, anti-nociceptive, human immunodeficiency strains of Mycobacterium tuberculosis, neuroprotective, anti-nociceptive, human immunodeficiency virus type-1 (HIV-1) inhibitory activity, in vitro anti-allergenic, and larvicidal activity against Aedes virus type-1 (HIV-1) inhibitory activity, in vitro anti-allergenic, and larvicidal activity against Aedes aegypti [11]. Kaempheria plant extracts and isolated compounds demonstrate numerous and promising aegypti [11]. Kaempheria plant extracts and isolated compounds demonstrate numerous and promising biological and pharmaceutical activities, which are summarized in Figure2. biological and pharmaceutical activities, which are summarized in Figure 2.

FigureFigure 2. 2.Reported Reported biological biological activities for for KaempheriaKaempheria species.species.

5.1. Anticancer Activity Rhizome ethanolic extracts of K. galanga and the purified component ethyl trans 5.1. Anticancer Activity p-methoxycinnamate (105) demonstrate moderate cytotoxic activity against human cholangiocarcinoma Rhizome ethanolic extracts of K. galanga1 and the purified component ethyl trans p- (CL-6) cells with IC50 of 64.2 and 49.4 µg mL− , respectively. Significant cholangiocarcinoma (CCA)methoxycinnamate efficacy as indicated (105) by suppressingdemonstrate tumormoderate growth cytoto and lungxic metastasisactivity against in CL6-xenografed human −1 micecholangiocarcinoma [15] is also observed. (CL-6) Swapana cells with et al. IC [1650] of documented 64.2 and 49.4 that K.μg galanga mL , isopimarenerespectively. diterpenoids,Significant cholangiocarcinoma (CCA) efficacy as indicated by suppressing tumor growth and lung metastasis sandaracopimaradiene-9α-ol (2), kaempulchraol I (14), and kaempulchraol L (17) exhibit promising in CL6-xenografed mice [15] is also observed. Swapana et al. [16] documented that K. galanga activity against human lung cancer with IC of 75 µM, 74 µM, and 76 µM, respectively, and mouth isopimarene diterpenoids, sandaracopimaradiene-950 α-ol (2), kaempulchraol I (14), and squamous cell carcinoma (HSC-2) inhibition with IC50 of 70 µM, 53 µM, and 58 µM, respectively [16]. kaempulchraol L (17) exhibit promising activity against human lung cancer with IC50 of 75 μM, 74 The latter compound, isolated from K. pulchra, is reported to have weak anti-proliferative activity μM, and 76 μM, respectively, and mouth squamous cell carcinoma (HSC-2) inhibition with IC50 of 70 againstμM, human53 μM, and pancreatic 58 μM, and respectively cervix cancers [16]. The [17 ].latter Chawengrum compound, et isolated al. [18] from stated K. that pulchra,K. pulchra is reportedlabdene diterpenoids,to have weak ( )-kolavelool anti-proliferative (81), and activity ( )-2β -hydroxykolaveloolagainst human pancreatic (82) exhibit and cytotoxic cervix cancers activity against[17]. − − 1 humanChawengrum leukemia et cells al. (HL-60)[18] stated with that IC K.50 pulchravalues labdene of 9.0 0.66diterpenoids, and 9.6 (−0.88)-kolaveloolµg mL− (,81 respectively), and (−)-2β [-18]. ± ± Acetone,hydroxykolavelool petroleum ether, (82) exhibit chloroform, cytotoxic and activity MeOH against extracts human of K. leukemia galanga rhizomes cells (HL-60) show with moderate IC50 cytotoxicityvalues of 9.0 in a± brine0.66 and shrimp 9.6 ± lethality0.88 μg mL bioassay−1, respectively compared [18]. with Acetone, vincristine petroleum sulfate ether, as chloroform, the reference compoundand MeOH [19 ].extracts Moreover, of K. a methanolicgalanga rhizomes extract show of K. moderate galanga rhizomes cytotoxi inducescity in a Ehrlichbrine shrimp ascites lethality carcinoma (EAC)bioassay cell death compared in a dose-dependent with vincristine mannersulfate as [20 the]. reference 5,7-Dimethoxyflavone compound [19]. (86 Moreover,) isolated froma methanolicK. galanga wasextract found of to K. reduce galanga cancer rhizomes resistance induces toEhrlich tyrosine ascites kinase carcin inhibitorsoma (EAC) (TKI) cell death by inhibiting in a dose-dependent breast cancer resistancemanner protein [20]. 5,7-Dimethoxyflavone (BCRP), one of the effl (ux86) transportersisolated from that K. increased galanga was efflux found of TKI toout reduce of cancer cancer cells. Thisresistance was observed to tyrosine both kinasein vitro inhibitorswith a dose-dependent (TKI) by inhibiting increase breast in cancer the intracellular resistance protein concentration (BCRP), of one of the efflux transporters that increased efflux of TKI out of cancer cells. This was observed both sorafenib in MDCK/BCRP1 breast cancer resistance cells, with an EC50 of 8.78 µM as well as in vivo byincreasing sorafenib AUC in mice tissues when co-administered with compound 88, as reported by kinetic results [21]. The isolated methyl-β-D-galactopyranoside specific lectin from the rhizome of K. rotunda exhibited in vitro antitumor activity against Ehrlich ascites carcinoma cells at a pH between 6–9 and a temperature range between 30–80 ◦C. Tumor inhibition was also observed in vivo in EAC-bearing mice [22]. Nutrients 2019, 11, 2396 5 of 33

The cytotoxicity of MeOH, petroleum ether, and EtOAc extracts against C33A cancer cells via MTT and scratch assays compared with essential oils of K. galanga rhizomes showed activity for the 1 EtOAc and MeOH fractions at 1000 µg mL− with 11% and 14% cell viability and weak efficacy with petroleum ether extracted essential oils in a MTT assay. Cell growth inhibition was observed with all extracts in the scratch assay [23]. Compound (140) isolated from K. angustifolia was described 1 to have strong activity with an IC50 of 1.4 µg mL− , which was comparable to 5-fluorouracil as a reference drug. Compound (138) also showed moderate inhibition against human lung cancer. 20-Hydroxy-4,40,60-trimethoxychalcone (flavokawain A; 119) exhibited potent activity against HL-60 and MCF-7 cell lines. The results of Tang et al. [24] revealed that flavokawain A (119) exhibited 1 cytotoxic activity against MCF-7 and HT-29 cell lines with GI50 values of 17.5 µM (5.5 µg mL− ) and 1 45.3 µM (14.2 µg mL− ), respectively. Kaempfolienol (65) and zeylenol (133) were also found to have 1 moderate activity against HL-60 and MCF-7 cells with IC50 values <30 µg mL− and against HL-60 1 only with an IC50 value of 11.6 µg mL− respectively [24].

5.2. Anti-Obesity Activity An ethanolic extract, a polymethoxyflavonoid-rich fraction (PMF) and a polymethoxyflavonoid-poor fraction from K. parviflora were screened against an obesity-induced dermatopathy system using Tsumura Suzuki obese diabetes (TSOD) mice as an obesity model (Hidaka, Horikawa, Akase, Makihara, Ogami, Tomozawa, Tsubata, Ibuki, and Matsumoto) [11]. The ethanolic extract reduced mouse body weight and the thickness of the subcutaneous fat layer more than the PMF fraction that is used as a dietary supplement in controlling skin disorders caused by obesity [11].

5.3. Anti-HIV Activity Viral protein R (Vpr) is one of the HIV accessory proteins that can be targeted for controlling viral replication and pathogenesis. A CHCl3 fraction of K. pulchra exhibits Vpr-inhibitory activity 1 at 25l g mL− . In addition, isopimarene type diterpenoids isolated from the rhizomes of the plants, kaempulchraol B (43), kaempulchraol D (45), kaempulchraol G (46), kaempulchraol Q (20), kaempulchraol T (36), kaempulchraol U (50), and W (22) inhibit the expression of Vpr at concentrations from 1.56 to 6.25 µM[25].

5.4. Antimicrobial Activity Arabietatriene (62) isolated from K. roscoeana exhibits antibacterial activity against Gram-positive bacteria Staphylococcus epidermidis and Bacillus cereus [26]. Anticopalic acid (72), anticopalol (77), and 8(17)-labden-15-ol (68) isolated from K. elegans also exhibited antibacterial activity against B. cereus [18]. Acetone, petroleum ether, chloroform, and MeOH extracts of K. galanga rhizomes exhibit moderate antibacterial activity against Gram-positive and Gram-negative bacteria in comparison with ciprofloxacin [19]. Ethyl p-methoxycinnamate (105) also isolated from K. galanga rhizomes have been shown based on a resazurin micro-titer assay to inhibit Mycobacterium tuberculosis H37Ra, H37Rv, multidrug-resistant, and drug-susceptible isolates with MIC 0.242–0.485 mM [27]. Its essential oil also displays strong antibacterial activity against Staphylococcus aureus and Salmonella typhimurium, and weak activity against Escherichia coli [28]. Moreover, essential oils extracted from three varieties of K. galanga exhibited potent larvicidal activity [29]. An ethyl acetate extract of K. rotunda inhibits S. aureus and E. coli [30]. A rhizomes extract of K. galanga inhibits Epstein–Barr virus with no cytotoxic effect in Raji cells [14]. In contrast, isolated diterpenoids from K. roscoeana exhibited no activity against Plasmodium falciparum (Chloroquine-resistant) [26]. Fauziyah et al. [31] described that an ethanolic extract of K. galanga alone exhibits 100% growth inhibition of the multi-drug resistant (MDR) 1 Mycobacterium tuberculosis (isolates at 500 µg mL− ). However, a combination of this extract with streptomycin, ethambutol, and isoniazid showed inhibition values of 55%, 76%, and 50%, respectively. Ethanol, methanol, petroleum ether, chloroform, and aqueous extracts of K. galanga rhizome showed antimicrobial activity against human pathogenic bacteria and fungi, while the ethanolic extract exhibited Nutrients 2019, 11, 2396 6 of 33 the strongest inhibition of S. aureus using an inhibition zone assay [32]. However, flavokawain A (119) and other compounds reported from K. angustifolia had no antimicrobial activity against tested microbes [24].

5.5. Antioxidant Activity

The CHCl3 and MeOH extracts of the rhizomes of K. angustifolia showed strong antioxidant activity against DPPH expressed with 615.92 mg trolox equivalent (TE)/g of extract. In an azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) assay, MeOH extracts showed good antioxidant properties with a value of 38.87 mg TE/g. However, n-hexane extract exhibited significant antioxidant activity with 901.76 mg TE/g in a cupric-reducing antioxidant capacity assay, while EtOAc extract exhibited significant reduction ability against ferric reducing antioxidant power (FRAP) with a value of 342.23 mg TE/g. Also, kaempfolienol (65) showed potent free radical scavenging activity in a DPPH assay, as well as, 20-hydroxy-4,40,60-trimethoxychalcone (119) in ABTS, CUPRAC, and FRAP assays [33,34]. A methanol extract of rhizomes of K. galanga exhibited a concentration-dependent antioxidant activity in DPPH, ABTS, and nitric oxide (NO) radical scavenging assays [20]. Moreover, the essential oil extracts of conventionally propagated and in vitro propagated K. galanga had significant DPPH radical scavenging activity [35]. As well, the ethanol extract of K. rotunda exhibited antioxidant 1 activity in a DPPH assay with IC50 (67.95 µg mL− )[30].

5.6. Anti-Inflammatory Activity The cyclohexane, chloroform, and ethyl acetate extracts with diarylheptanoids isolated from K. galanga showed a pronounced inhibition of Lipopolysaccharides (LPS)-induced nitric oxide in macrophage RAW 264.7 cells compared with indomethacin [13]. The EtOH extract and compounds (1, 52, 53, 119, 120) isolated from K. marginata had promising anti-inflammatory activity based on the suppression of NO production and inducible nitric oxide synthase (iNOS) mRNA and cyclooxygenase-2 (COX-2) genes expression [36,37]. Diterpenoids (9–10) isolated from K. pulchra had topical anti-inflammatory activity in 12-O-tetradecanoylphorbol-13-acetate-induced ear edema in rats with ID50 330 and 50 µg/ear, respectively. Biological activity may be due to the activation of Maxi-K channels in neurons and smooth muscles [38]. The ethanol extract of K. parviflora exhibited potent inhibition of PGE2. The plant extract and 30,40,5,7-tetramethoxyflavone (86) were also reported to exhibit a dose-dependent inhibition of iNOS-mRNA expression. Additionally, H2O, EtOH, EtOAC, CHCl3, and n-hexane soluble sub-fractions exhibited good in vivo anti-inflammatory activity by decreasing rat paw edema [39]. An 80% EtOH extract reduced UV-induced COX-2 expression in mice skin that was attributed to the anti-oxidative activity of polyphenolics against the oxidizing properties of UV radiation [40]. A 60% EtOH and EtOAc-soluble fraction of 100% methanol extracts of K. parviflora decreased knee osteoarthritis, which was likely due to methoxylated flavones [41]. Ethyl p-methoxycinnamate (105) isolated from K. galana inhibited cytokines as IL-1 and TNFα and endothelial function in rats [42]. Tewtrakul, et al. [43] found that the isolated methoxylated flavonoids from K. parviflora, 5-hydroxy-3,7,30,40-tetramethoxyflavone (96), 5-hydroxy-7,40-dimethoxyflavone (93), and 5-hydroxy-3,7,40-trimethoxyflavone (95) exhibited anti-inflammatory activity against the PGE2 production, with IC50 values of 16.1 µM, 24.5 µM, and 30.6 µM, respectively [43]. Tewtrakul and Subhadhirasakul [44] described methoxyflavones 96, 93, and 95 from a hexane extract of K. parviflora rhizomes that exhibited activity against NO release in RAW264.7 cells with IC50 values of 16.1 µM, 24.5 µM, and 30.6 µM, respectively. In addition, 5-hydroxy-3,7,30,40-tetramethoxyflavone (96) inhibited PGE2 release with an IC50 value of 16.3 µM, with negative activity on Tumor Necrosis Factor alpha (TNF-α) with IC50 >100 µM[44]. Petroleum ether extract from K. galanga was active against acute 1 inflammation at 300 mg/kg in rats and inhibited the inflammation and MPO levels at 100 mg kg− in the chronic model [45]. Nutrients 2019, 11, 2396 7 of 33

5.7. Anticholinesterase Activity According to Sawasdee et al. [46], a MeOH extract as well as compounds (86–87) isolated from K. parviflora rhizomes inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with greater cholinesterase inhibitory toward AChE and BChE for (86), which was an observation of significance in the treatment of Alzheimer’s disease [46].

5.8. Anti-Mutagenicity Activity

CH2Cl2 and EtOAc soluble fractions of K. parviflora showed anti-mutagenicity and α-glucosidase inhibitory activity. Isolated methoxylated compounds (86, 97, 84, and 92) from these extracts exhibited potent activity with IC50 values of 0.40, 0.40, 0.42, and 0.47 nmol/plate, respectively. Compounds (88, 87, and 91), also showed significant activity with IC50 values of 20.4 µM, 54.3 µM, and 64.3 µM, respectively [47].

5.9. Effect on Cytochromes CYP 450 The results listed by Ochiai et al. [48] stated that the continued ingestion of (88) isolated from K. parviflora decreases liver CYP3A expression, which in turn increased levels of compounds metabolized by CYP3As such as midazolam [48].

5.10. Vascular Activity

The oral administration of CH2Cl2 extract of K. parviflora in middle-aged rats was found to decrease vascular responses to phenylephrine, increase acetylcholine-induced vasorelaxation and the production of nitric oxide (NO) from blood vessels, and decrease visceral, subcutaneous fat, fasting serum glucose, triglyceride, and liver lipid accumulation [49]. The effect of intravenous administration of a CH2Cl2 extract of K. galanga to rats reduced the mean arterial blood pressure [50]. This anti-hypertensive effect was attributed to ethyl cinnamate, which is a major compound in the extract [50]. The ethanol extract of rhizomes of K. parviflora caused dose-dependent relaxation on aortic rings as well as ileum pre-contracted with phenylephrine and acethylcholine [51].

5.11. Adaptogenic Activity Hexane, chloroform, methanol, and ethanol extracts of K. parviflora exhibited adaptogenic activity compared with a crude ginseng root powder used as a reference [52]. A single oral dose of K. parviflora rhizome (60% EtOH extract) increased the whole-body potential expenditure in humans [53]. K. parviflora was also found to improvement physical fitness and health by decreasing oxidative stress [54].

5.12. Xanthine Oxidase Inhibitory Activity Among the isolated methoxylated flavonoids from K. parviflora,(87 and 86) inhibit xanthine oxidase activity with IC50 values of 0.9 and >4 mM, respectively [9].

5.13. Allergenic Activity

Isolated polymethoxyflavones from K. parviflora (86, 97), in addition to CH2Cl2, EtOAc, and H2O extracts, alleviated type I allergy symptoms through suppressing Rat Basophilic Leukemia cells (RBL-2H3) cell degranulation, with (92) and (94) showing the highest anti-allergenic activity [55].

5.14. Neurological Activity A methanolic extract (95% MeOH) of K. parviflora exhibited neuroprotective activity by increasing rat hippocampus serotonin, norepinephrine, and dopamine levels in comparison with a vehicle-treated group [56]. An acetone extract of K. galanga rhizomes and leaves also exhibited central nervous system depressant activity [57]. Nutrients 2019, 11, 2396 8 of 33

5.15. Nociceptive Activity. A K. galanga rhizome extract exhibited anti-nociceptive activity in rats that was stronger than aspirin but weaker than morphine. The efficacy was abolished by naloxone, suggesting that the analgesic effect may be centrally and peripherally mediated [58].

5.16. Wound-Healing Activity The co-administration of a K. galanga rhizomes extract (95% EtOH) with dexamethazone was found to have wound-healing activity in mice comparable to dexamethazone only [59].

5.17. Effects on Sexual Performance Several 7-methoxyflavones (86, 87, 89, 91, 93–95) isolated from K. parviflora rhizomes improved sexual activity in males through the inhibition of PDE5, with 86 being the most potent [60]. The activity was attributed to methoxyls present at positions C5 and C7 [60]. K. parviflora rhizome extracts, standardized to 5% DMF, also improve erectile function in healthy men [61]. A K. parviflora extract as well as 5,7-dimethoxyflavones augment testosterone production, which decreases age-related diseases and hypogonadism [62]. Improved testosterone levels, sperm count, and sexual performance was observed in streptozotocin (STZ)-induced diabetic rats when treated with a K. parviflora extract (aqueous with 1% Tween-80) [63].

5.18. Miscellaneous The rhizome extract (95% ethanolic) of K. parviflora reduced obesity via the inhibition of adipogenesis, lipogenesis, and muscle atrophy in mice [64]. In contrast, the K. parviflora derivatives of 5-hydroxy-7-methoxyflavone induce skeletal muscle hypertrophy [65]. A K. parviflora extract (95% EtOH) served as a potential anti-acne agent with anti-inflammatory, sebostatic, and anti-propioni bacteria activity [66]. 1 Recently, K. parviflora alcoholic extract at 3–30 µg mL− was evaluated regarding the molecular mechanisms associated with rheumatoid arthritis for up to 72 h compared with the dexamethasone as positive control [67]. They documented that the EtOH extract significantly decreased the gene expression levels of pro-inflammatory cytokines, inflammatory mediators, and matrix-degraded enzymes, but neither induced apoptosis nor altered the cell cycle. They also reported that the alcoholic extract inhibits cell migration, reduces the mRNA expression of cadherin-11, and selectively reduces the phosphorylation of mitogen-activated protein kinases (P38, MAPKs), signal transducers, and activators of transcription 1 (STAT1) and 3 (STAT3) signaling molecules, without interfering with the NF-κB pathway [67]. A K. galanga extract (acetone, petroleum ether, chloroform, or methanolic) exhibited dose-dependent anthelmintic activity with strong paralytic activity within one hour and death 1 within 80 min at a 25 mg mL− concentration [68].

6. Chemical Metabolites of Kaempferia Species Chemical profiles of Kaempferia exhibited the presence of different types of secondary metabolites such as terpenoids, especially isopimarane phenolic compounds, diarylheptanoids [13], flavonoids [69–71], and essential oils [72,73]. This review summarized the reported variety of compound types, including isopimarane, abietane, labdan, and clerodane diterpenoids, flavonoids, phenolic acids, phenyl-heptanoids, curcuminoids, tetrahydropyrano-phenolic, and steroids. Diterpenoids, especially isopimarane types, were the most reported compounds from the plants of this genus, in addition to phenolics, flavonoids, and essential oils. Each class will be described and listed in the following items, and the structures will be summarized in Tables1–3. Nutrients 2019, 11, 2396 9 of 33

Nutrients 2019, 11, 2396 10 of 38

TableTable 1. 1.Diterpenoids. Diterpenoids.

No NameNo Name R R1 1 R R22R R 3R R3 4R R5 R4 6 RR5 7R PlantR6 R7Ref Plant Ref

1 Sandaracopimaradiene1 Sandaracopimaradiene H H H HH HH H H HHK. galanga H H HH K. galanga K. roscoeana K. roscoeana 2 Sandaracopimaradiene-9α-ol α-OH H H H H H H H K. marginata 2 Sandaracopimaradiene-9α-ol α-OH H H H H H HK. marginataH 3 8(14),15-Sandaracopimaradiene-1α,9α-diol α-OH H α-OH H H H H H K. galanga K. pulchra 4 1,11-Dihydroxypimara-8(14),15-diene H H α-OH H H α-OH H H 3 8(14),15-Sandaracopimaradiene-1α,9α-diol α-OH H α-OH H H H H K. galanga H K. sp. [4,16,17,25,26,36,74–76] K. pulchra K. galanga 5 6β-Hydroxypimara-8(14),15-diene-1-one H β-OH =OHHHHH 4 1,11-Dihydroxypimara-8(14),15-diene H α-OH H H H α-OH H H K. [4,16,17,25,26,36,74–76]K. marginata sp. 6 Sandaracopimaradien-6β,9α-diol-l-one α-OH β-OH =OHHHHH K. galanga K. galanga 5 β-Hydroxypimara-8(14),15-diene-1-one6 β-OHH =O H H H H H 7 Boesenberol I α-OH H =OHHH K. marginataα-OH H

8 Boesenberol6 J Sandaracopimaradien-6β,9α-diol-l-oneα-OH α-OHβ-OH β-OH =OHHHHH=O H H H H H K. galanga K. galanga 7 Boesenberol I α-OH H =O H H α-OH H H K. roscoeana 9 Sandaracopimaradien-1α,2α-diol H H α-OH α-OH H H H H K. pulchra 8 Boesenberol J α-OH β-OH =O H H H H K. galanga H K. marginata K. roscoeana K. pulchra [26,38,75] 10 2α-Acetoxy-sandaracopimaradien-1α-ol H H α-OH α-OAc H H H H 9 Sandaracopimaradien-1α,2α-diol H Hα-OH α-OH H H H K. H pulchra K. marginata [26,38,75] K. marginata K. galanga 11 Kaempulchraol E α-H β-OH α-OH H H H H H K. pulchra 10 α-Acetoxy-sandaracopimaradien-12 α-ol H Hα -OH α-OAc H H H K. H pulchra 12 Kaempulchraol F H H α-OH H α-OH H H H K. pulchra

13 Kaempulchraol H H β-OH α-OH H α-OH H H H K. galanga 14 Kaempulchraol I H H α-OH H H H H H K. pulchra K. roscoeana 15 Kaempulchraol J H H α-OH H H H =O K. pulchra 16 Kaempulchraol K α-OH β-OAc H H H H H H [4,16,17,25,26,74] K. galanga 17 Kaempulchraol L α-OMe β-OH H H H H H H K. pulchra 18 Kaempulchraol M α-OH H α-OH α-OH H H H H 19 Kaempulchraol P H β-OH H H H H H H 20 Kaempulchraol Q α-OAc β-OH H H H H H H K. pulchra 21 Kaempulchraol R α-OH H H H H H α-OAc H Nutrients 2019, 11, 2396 10 of 33

Table 1. Cont.

No Name R R1 R2 R3 R4 R5 R6 R7 Plant Ref 22 Kaempulchraol T H β-OH H H H H α-OAc H 23 Kaempulchraol V α-OH β-OH H H H H β-OAc H 24 Kaempulchraol W α-OH β-OH H H H H β-OH H 25 9 α-Hydroxyisopimara-8(14),15-dien-7-one α-OH H H H H H =OH

26Nutrients 7β,9 α-Dihydroxypimara-8(14),15-diene 2019, 11, 2396 Nutrients 2019, 11,α 2396-OH H H H H H β-OH12 of 38 H 12 of 38 27 Isopimara-8(14),15-dien-7-one H H H H H H =OH K. roscoeana [26] 28 (1S,5S,9S,10S,11R,13R)-1,11-Dihydroxypimara-8(14),15-diene H H α-OH H H K. pulchraα -OH H H K. pulchraK. roscoeana K. marginata R S S S S 31R R Sandaracopimaradien-α-ol-l-one 9 31 α-OH Sandaracopimaradien-H =O α-ol-l-one 9H Hα-OH HH =O H HH H H H H 29 (1 ,2 ,5 ,9 ,10 ,11 ,13 )-1,2,11-Trihydroxypimara-8(14),15-diene HH α-OH α-OH H α-OH H H K. pulchra [4,17,25,26,74,75] 32 β-Acetoxysandaracopimaradien-96 α-ol-l-one 32 α-OH β-Acetoxysandaracopimaradien-96 β-OAc =O α H-ol-l-one H α-OH β-OAc H =O H H H H H H HK. roscoeana 30 7α-Hydroxyisopimara-8(14),15-diene H H H H HK. H α-OH H K. 33 Sandaracopimaradien-6β,9α-diol-l-one 33 α-OH βSandaracopimaradien-6-OH =O β,9α-diol-l-one H H α-OH β H-OH =O H spH H H [76] H H sp HK. pulchra [76]

31 Sandaracopimaradien-34 β-Acetoxysandaracopimaradien-l6 9α-ol-l-one α,9α-diol 34 α-OH αβ-OH-Acetoxysandaracopimaradien-l6 β-OAc α-OH H Hα ,9α-diol=OHHHHH H α-OH Hβ -OAc α-OH H H H H H H H 32 6β-Acetoxysandaracopimaradien-9α-ol-l-one α-OH β-OAc =OHHHHH 35 Sandaracopimaradien- lα,6β,9α-triol35 α -OH β-OHSandaracopimaradien- α-OH H lα,6β,9α H-triol α -OH Hβ -OH α-OH H H H H H H H K. sp 33 Sandaracopimaradien-6β,9α-diol-l-one α-OH β-OH =OHHHHH 36 Roscorane B 36 H RoscoraneH B H α-OHH HH H OH H H α-OHH HH OH [76] 34 6β-Acetoxysandaracopimaradien-l37 Roscoraneα,9α-diol C 37 α-OHβ-OHH β-OAcHRoscorane OH Cα -OH H Hβ H-OH H H HH OH K. roscoeana OH H H H [26] H H H OH K. roscoeana [26]

35 Sandaracopimaradien-38 lα,6β,9Roscoraneα-triol D 38 α-OH H β-OHRoscoraneH Dα -OHH OH HH H OH H HH HHOH OH H H OH H H OH

36R(1 Roscorane,2S,5S,7S,9R,10 BS,13R)-1,2,7-Trihydroxypimara- R(1,2S H,5S,7S,9R,10S,13R)-1,2,7-Trihydroxypimara- H H H H α-OH H OH 39 39 H H α-OHH H H Hβ -OH HH α-OHH H H β-OH H K. roscoeana 37 Roscorane8(14),15-diene C H 8(14),15-dieneβ-OH H OH H H OH H [26]

38 RoscoraneS,5(1S,7R D,9R,10S,11R,13R)-1,7,11- HS,5(1S,7R,9R,10S H,11R,13R)-1,7,11- H OH HK. marginata H OH OH K. marginata 40 40 H β-OH H H H H βα H-OH-OH H H H H [75] α H-OH H [75] 39 (1R,2S,5S,7S,9R,10S,13R)-1,2,7-Trihydroxypimara-8(14),15-dieneTrihydroxypimara-8(14),15-diene Trihydroxypimara-8(14),15-diene H H H α-OH H H β-OH H K. marginata 40 (1S,5S,7R,9R,10S,11R,13R)-1,7,11-Trihydroxypimara-8(14),15-dieneR(1,2S,5S,7S,9R,10S,13R)-1,2-Dihydroxypimara- R(1,2HS,5S,7S,9R,10S,13βR-OH)-1,2-Dihydroxypimara- H H H H α-OH H [75] 41 41 H H α-OHH H H H HH α-OHH H H H 8(14),15diene-7-one 41 (1R,2S,5S,7S,9R,10S,13R)-1,2-Dihydroxypimara-8(14),15diene-7-one HHH8(14),15diene-7-one α-OH H H H H

52–54 42–51 52–54 52–54 42–51 42–51 No Name R1 R2 R3 R4 Plant Ref No Name No 1 R 2 NameR 3 R14 R R Plant2 R 3Ref R 4 R Plant Ref 42 Kaempulchraol A H β-OH H α-OMe K. pulchra [4,17,25,74] 42 Kaempulchraol A42 KaempulchraolHβ-OH A H α-OMe K. pulchraHβ-OH [4,17,25,74]H α-OMe K. pulchra [4,17,25,74] 43 Kaempulchraol B H β-OH H β-OMe 43 Kaempulchraol B43 KaempulchraolHβ-OH B H β-OMe Hβ-OH H β-OMe 44 Kaempulchraol C H β-OH H α-OH 45 Kaempulchraol D H β-OH H β-OH 46 Kaempulchraol G H β-OH H =O Nutrients 2019, 11, 2396 11 of 33 Nutrients 2019,, 1111,, 23962396 13 of 38

44 Kaempulchraol C Hβ-OH H α-OH 44 Kaempulchraol C Hβ-OH H α-OH 45 Kaempulchraol D Table 1. Hβ-OHCont. H β-OH 45 Kaempulchraol D Hβ-OH H β-OH 46 Kaempulchraol G Hβ-OH H =O No Name46 Kaempulchraol R G R1 R2 Hβ-OH R 3 R4 H R5 =O R6 R7 Plant Ref 47 Kaempulchraol N α-OH β-OH H α-OH 47 Kaempulchraol47 N Kaempulchraol N α-OH α-OH β-OHβ-OH H α-OH H α-OH 48 Kaempulchraol O α-OH β-OH H β-OMe 48 Kaempulchraol48 O Kaempulchraol O α-OH α-OH β-OHβ-OH H β-OMe H β-OMe 49 Kaempulchraol S H H α-OH =O 49 Kaempulchraol49 SKaempulchraol S H H H H α-OH= O =Oα -OH 50 Kaempulchraol U H H α-OH H 50 Kaempulchraol50 UKaempulchraol U HH HH α-OH H Hα -OH 51 Isopimara-8(9),15-dien-7-one H H K. =Oroscoeana H [26] 51 Isopimara-8(9),15-dien-7-one51 Isopimara-8(9),15-dien-7-one H H H H =OHK. =Oroscoeana H K.[26] roscoeana [26] 52 8(14),15-Isopimaradiene-6α-ol H α-OH H --- 52 8(14),15-Isopimaradiene-652 α-ol8(14),15-Isopimaradiene-6α-ol H H α-OHα-OH H H--- — 53 α-Acetoxy-sandaracopimaradiene1 α-OAc H H K.- marginata K.[36] marginata [36] 53 1α-Acetoxy-sandaracopimaradiene53 α-Acetoxy-sandaracopimaradiene1 α-OAc α-OAc HH H HK.- marginata - [36] 54 α-Acetoxy-sandaraco1 pimaradien-2-one α-OAc =O H - 54 1α-Acetoxy-sandaraco54 pimaradien-2-oneα-Acetoxy-sandaraco1 pimaradien-2-oneα-OAc α-OAc =OH-=O H - No Name Structure Plant Ref No NameNo Name Structure Structure Plant Plant Ref Ref

55 R)-ent-2-Hydroxyisopimara-8(14),15-diene(2 K. pulchra [4,17,25,74] 55 (2R)-ent-2-Hydroxyisopimara-8(14),15-diene55 R)-ent-2-Hydroxyisopimara-8(14),15-diene(2 K. pulchra K. pulchra [4,17,25,74] [4,17,25,74]

56 Kaemgalangol A K. galanga [16] 56 Kaemgalangol56 A Kaemgalangol A K. galanga K. galanga [16] [16]

Nutrients 2019, 11, 2396 14 of 38

57 Roscorane57 A Roscorane A K. roscoeana K. roscoeana [26] [26]

58 R=OMe; Roscotane A

59 R=H; Roscotane B

K. roscoeana [26]

60 Roscotane C

Nutrients 2019, 11, 2396 14 of 38 Nutrients 2019, 11, 2396 14 of 38

Nutrients 2019, 11, 2396 12 of 33

57 Roscorane A K. roscoeana [26] 57 Roscorane A K. roscoeana [26] Table 1. Cont.

No Name R R1 R2 R3 R4 R5 R6 R7 Plant Ref

58 R=OMe; Roscotane A 58 R=OMe; Roscotane58 A R=OMe; Roscotane A

59 R=H; Roscotane B 59 R=H; Roscotane B

59 R=H; Roscotane B

K. roscoeana [26] K. roscoeana [26]

60 Roscotane C 60 Roscotane60 C Roscotane C

K. roscoeana [26]

NutrientsNutrients 2019 2019, ,11 11, ,2396 2396 1515 ofof 3838

61 Roscotane6161 D RoscotaneRoscotane D D

62 R=H; Ar-abietatriene 62 R=H; Ar-abietatriene62 R=H; Ar-abietatriene 63 R=[=O]; 7-Dehydroabietanone6363 R=[=O];R=[=O]; 7-Dehydroabietanone 7-Dehydroabietanone

64 R=α-OH; Abieta-8,11,13-trien-7α-ol 6464 αα-OH;-OH;R=R= Abieta-8,11,13-trien-7 Abieta-8,11,13-trien-7αα-ol-ol

6565 KaempfolienolKaempfolienol K.K. angustifolia angustifolia [33,34][33,34]

Nutrients 2019, 11, 2396 15 of 38

61 Roscotane D

62 R=H; Ar-abietatriene 63 R=[=O]; 7-Dehydroabietanone

Nutrients 2019, 11, 2396 13 of 33

64 α-OH;R= Abieta-8,11,13-trien-7α-ol Table 1. Cont.

No Name R R1 R2 R3 R4 R5 R6 R7 Plant Ref

65Nutrients Kaempfolienol65 2019 , 11, 2396 Kaempfolienol K. angustifolia K. angustifolia [33,34]16 of 38 [33,34]

Nutrients 2019, 11, 2396 16 of 38 NutrientsNutrients 2019 2019, 11, 11, 2396, 2396 1616 of of 38 38

66 Z(12,14R)-Labda-8(17),12-dien-14,15,16-triol K. roscoeana [26]

66 Z(12,14R)-Labda-8(17),12-dien-14,15,16-triol K. roscoeana [26] 66 (12Z,14R)-Labda-8(17),12-dien-14,15,16-triol6666 Z(12,14Z(12,14R)-Labda-8(17),12-dien-14,15,16-triolR)-Labda-8(17),12-dien-14,15,16-triol K.K. roscoeana roscoeana K. roscoeana [26][26] [26]

67 Propadane A

K. elegans 67 Propadane A 67 Propadane6767 A PropadanePropadane A A 68 R=H --- 8(17)-Labden-15-ol K. elegans

[18] K. elegans K.K. elegans elegans 69 R=OH; Propadane B 68 R=H --- 8(17)-Labden-15-ol 68 R=H — 8(17)-Labden-15-ol68 R=H --- 8(17)-Labden-15-ol 69 R=OH; Propadane B [18] [18][18] 69 R=OH; Propadane B [18] 6969 R=OH;R=OH; Propadane Propadane B B

70 Propadane70 C Propadane C K. pulchra K. pulchra

Nutrients 2019, 11, 2396 17 of 38

70 Propadane C K. pulchra 70 Propadane C K. pulchra

71 Cleroda-2,4(18),14-trien-13-ol71 Cleroda-2,4(18),14-trien-13-ol K. pulchra K. pulchra

72 R=H; Anticopalic acid

73 R=Me; Methyl anticopalate

K. elegans

74 (+)-15,16-Eoxy-8(17),13(16),14-labdatriene [18]

Nutrients 2019, 11, 2396 17 of 38 Nutrients 2019, 11, 2396 17 of 38

Nutrients 2019, 11, 2396 14 of 33

71 Cleroda-2,4(18),14-trien-13-ol K. pulchra 71 Cleroda-2,4(18),14-trien-13-ol K. pulchra

Table 1. Cont.

No Name72 R=H; Anticopalic R acid R1 R2 R3 R4 R5 R6 R7 Plant Ref

72 R=H; Anticopalic acid 72 R=H; Anticopalic acid

73 R=Me; Methyl anticopalate 73 R=Me; Methyl73 anticopalate R=Me; Methyl anticopalate

K. elegans K. elegans K. elegans

74 (+)-15,16-Eoxy-8(17),13(16),14-labdatriene74 (+)-15,16-Eoxy-8(17),13(16),14-labdatriene [18] 74 (+)-15,16-Eoxy-8(17),13(16),14-labdatriene [18][ 18]

Nutrients 2019, 11, 2396 18 of 38

75 (+)-Pumiloxide75 (+)-Pumiloxide

76 13-Oxo-14,15-bis-nor-labd-8(17)-ene76 13-Oxo-14,15-bis-nor-labd-8(17)-ene

77 Anticopalol K. elegans

Nutrients 2019, 11, 2396 18 of 38

75 (+)-Pumiloxide

Nutrients 2019, 11, 2396 15 of 33 76 13-Oxo-14,15-bis-nor-labd-8(17)-ene

Table 1. Cont.

No Name R R1 R2 R3 R4 R5 R6 R7 Plant Ref

77 Anticopalol77 Anticopalol K. elegans

Nutrients 2019, 11, 2396 19 of 38 Nutrients 2019, 11, 2396 19 of 38 Nutrients 2019, 11, 2396 19 of 38

78 Labda-8(17),13(14)-diene-15,16-olide 78 Labda-8(17),13(14)-diene-15,16-olide78 Labda-8(17),13(14)-diene-15,16-olide K. elegans

79 (+)-Labda-8(17),13(Z)-diene-15,16-diol 79 (+)-Labda-8(17),13(Z)-diene-15,16-diol79 (+)-Labda-8(17),13(Z)-diene-15,16-diol

80 Calcaratarin A 80 Calcaratarin80 A Calcaratarin A

K. pulchra K. pulchra 81 R=H; (-)-Kolavelool81 R=H; (-)-Kolavelool K. pulchra K. pulchra 81 R=H; (-)-Kolavelool 82 R= β-OH; (-)-2β-Hydroxykolavelool82 β-OH;R= (-)-2β-Hydroxykolavelool 82 β-OH;R= (-)-2β-Hydroxykolavelool [18] [18][18 ]

83 β-OMe;R= Dysoxydensin E 83 β-OMe;R= Dysoxydensin E 83 R=β-OMe; Dysoxydensin E

Nutrients 2019, 11, 2396 16 of 33

Table 1. Cont. Nutrients 2019, 11, 2396 20 of 38

No Name R R1 R2 R3 R4 R5 R6 R7 Plant Ref

84 13-Epi-roseostachenone84 13-Epi-roseostachenone

H OH HO 85 (+)-13-Epi-2α-hydroxykolavelool85 (13-epi-roseostachenol)(+)-13-Epi-2α-hydroxykolavelool (13-epi-roseostachenol) K. pulchra K. pulchra

Nutrients 2019, 11, 2396 17 of 33

Nutrients 2019, 11, 2396 Nutrients 2019Nutrients, 11, 2396 2019 , 11, 2396 21 of 38 21 of 38 21 of 38

TableTable 2. 2. FlavonoidsFlavonoids and phenolics and ( phenolicsFlavonoids).Table (Flavonoids). 2. FlavonoidsTable 2. Flavonoids and phenolics and (phenolicsFlavonoids). (Flavonoids).

98–101 86–97 86–97 86–97 86–97 98–101 98–101 98–101 102–103 102–103 102–103 102–103

No Name R1 R2 R3 R4 Plant Ref No Name No 1 No R 2 RName 3 RName 4 R1 1 R 2 R R Plant2 3R R 3 R4 RRef4 RPlant Plant Ref Ref 86 5,7-Dimethoxyflavone H Me H H 86 5,7-Dimethoxyflavone 86 86 H5,7-Dimethoxyflavone 5,7-DimethoxyflavoneMe H H H H Me Me H H H H 87 4‘,5,7-Trimethoxyflavone H Me H OMe 87 ‘,5,7-Trimethoxyflavone4 87 87 H‘,5,7-Trimethoxyflavone 4 ‘,5,7-Trimethoxyflavone4 Me H H OMe H Me Me H H OMe OMe 88 3‘,4‘,5,7-Tetramethoxyflavone H Me OMe OMe 88 ‘,4‘,5,7-Tetramethoxyflavone3 88 88 ‘,4H‘,5,7-Tetramethoxyflavone3 ‘,4‘,5,7-Tetramethoxyflavone3 Me OMe H OMe H Me Me OMe OMe OMe OMe 89 3,5,7-Trimethoxyflavone OMe Me H H 89 3,5,7-Trimethoxyflavone 89 89 OMe3,5,7-Trimethoxyflavone 3,5,7-TrimethoxyflavoneMe H OMe H OMe Me Me H H H H 90 3,5,7,4‘-Tetramethoxyflavone OMe Me H OMe 90 3,5,7,4‘-Tetramethoxyflavone 90 90 OMe3,5,7,4 ‘-Tetramethoxyflavone3,5,7,4‘-TetramethoxyflavoneMe H OMe OMeOMe Me Me H H OMe OMe 91 3,5,7,3‘,4‘-Pentamethoxyflavone OMe Me OMe OMe 91 3,5,7,3‘,4‘-Pentamethoxyflavone 91 91 OMe3,5,7,3‘ ,4‘-Pentamethoxyflavone3,5,7,3‘,4‘-PentamethoxyflavoneMe OMe OMe OMeOMe Me Me OMe OMe OMe OMe 92 5-Hydroxy-7-methoxyflavone H HK. parviflora H [9,55,71,77] H K. parvifloraK.K. parviflora parviflora [9,55,71,77][9,55,71 ,[9,55,71,77]77 ] 92 5-Hydroxy-7-methoxyflavone92 92 5-Hydroxy-7-methoxyflavone H 5-Hydroxy-7-methoxyflavone H H H H H H H H H H H 93 5-hydroxy-7,4‘-dimethoxyflavone H H H OMe 93 5-hydroxy-7,4‘-dimethoxyflavone 93 93 H5-hydroxy-7,4 ‘-dimethoxyflavone5-hydroxy-7,4H‘-dimethoxyflavone H H OMe H H H H H OMe OMe 94 5-Hydroxy-3,7-dimethoxyflavone OMe H H H 94 5-Hydroxy-3,7-dimethoxyflavone94 94 5-Hydroxy-3,7-dimethoxyflavone OMe 5-Hydroxy-3,7-dimethoxyflavone H H OMe H OMe H H H H H H 95 5-Hydroxy-3,7,4‘-trimethoxyflavone OMe H H OMe 95 5-Hydroxy-3,7,4‘-trimethoxyflavone 95 95OMe 5-Hydroxy-3,7,4 ‘5-Hydroxy-3,7,4-trimethoxyflavone H‘-trimethoxyflavone H OMe OMeOMe H H H H OMe OMe 96 5-Hydroxy-3,7,3‘,4‘-tetramethoxy flavone OMe H OMe OMe 96 5-Hydroxy-3,7,3‘,4‘-tetramethoxy flavone 96 965-Hydroxy-3,7,3 OMe 5-Hydroxy-3,7,3‘,4‘-tetramethoxy‘,4 H‘-tetramethoxy flavone OMe flavone OMe OMe OMe H H OMe OMe OMe OMe 97 5,3‘-Dihydroxy-3,7,4‘-trimethoxyflavone OMe H OH OMe 97 ‘5,3-Dihydroxy-3,7,4‘-trimethoxyflavone 97 97‘OMe5,3-Dihydroxy-3,7,4 ‘5,3-Dihydroxy-3,7,4‘-trimethoxyflavone H ‘-trimethoxyflavone OH OMe OMeOMe H H OH OH OMe OMe 98 Kaempferol H OH - - 98 Kaempferol 98 98 H KaempferolKaempferol OH - H - H OH OH - - - K. galanga- K. galanga K. galanga 99 Kaempferide H OMe - K. galanga 99 Kaempferide Nutrients99 2019, 1199, 2396 H KaempferideKaempferideOMe - H H OMe OMe - [42] - [42] [42] 22 [42]of 38 100 Tectochrysin Me H - - 100 Tectochrysin 100 100 Me TectochrysinTectochrysin H - Me K. parviflora- Me H H - - K. parviflora- K. K. parviflora parviflora- 101 Genkwanin101 Genkwanin Me OH Me OH - - -- [46] [46]

102 Pinocembin102 Pinocembin H - H -- - - - 103 Pinostrobin Me - - - 103 Pinostrobin Me - - -

K. parviflora [71] K. parvifloraK. angustifolia [71] K. angustifolia 104 Sakuranetin 104 Sakuranetin

105 ″,22″-Dimethylpyrano-[5″,6″:8,7]-flavone K. pulchra [18]

Nutrients 2019, 11, 2396 22 of 38

101 Genkwanin Me OH - - [46]

102 Pinocembin H - - -

103 Pinostrobin Me - - -

K. parviflora Nutrients 2019, 11, 2396 [71] 18 of 33 K. angustifolia 104 Sakuranetin

Cont. Table 2.

No Name R1 R2 R3 R4 Plant Ref

105 2”,2”-Dimethylpyrano-[5”,6”:8,7]-flavone105 ″,22″-Dimethylpyrano-[5″,6″:8,7]-flavone K. pulchraK. pulchra [18][ 18]

Nutrients 2019, 11, 2396 Nutrients 2019, 11, 2396 23 of 38 23 of 38

Nutrients 2019, 11, 2396 Nutrients 2019, 11, 2396 23 of 38 23 of 38 Nutrients 2019, 11, 2396 23 of 38

114–115 114–115 114–115 114–115 114–115 106–109 106–109 110–113 110110–113–113 114–115 106–109106–109 106–109110 –113 110–113 106–109 110–113

116–117 118–119 118–119118–119 116–117 116–117 118–119 118–119 106 Ethyl trans-p-methoxycinnamate116–117 116–117 H OMe CH2Me 118–119 No Name No 1 R Name 2 116R–117 1 3 R R 2 PlantR 3 RRef Plant Ref 107No FerulicName acid No 1 R Name2 R OMe13 R R OHPlant2 R3 RefR H Plant Ref 106 Ethyltrans- p-methoxycinnamate106 EthyltransNoH - p- methoxycinnamate Name OMe 2MeH 1 CH R OMe 2 2MeR CH3 RPlant [13] Ref 108 106 transEthyl-transp-Hydroxy-cinnamic- p-methoxycinnamate acid 106 HEthyl trans- p-methoxycinnamate H OMe 2Me H CH OH OMe 2Me H CH 107 Ferulic acid 107 106 OMeFerulic acidEthyltrans - p-methoxycinnamate OH OMe H H OH OMe 2Me H CH 109 107 trans-p-MethoxyFerulic cinnamic acid acid107 OMe Ferulic acid H OH OMe H H OH CH2Me H 108 trans-p-Hydroxy-cinnamic acid108 trans-107p-Hydroxy-cinnamic H acid Ferulic acid OH H H OMe OH OH[13] H H [13] [13] K. galanga 110 108 transp--Hydroxybenzoicp-Hydroxy-cinnamic acid acid 108 trans H-p -Hydroxy-cinnamic acid H OH H OH H OH COOH H [13] [13] 109 trans-p-Methoxy cinnamic acid109 trans-108p-Methoxy H cinnamictrans-p-Hydroxy-cinnamic acid H acid 2Me H K. CH Hgalanga H 2Me OH K. CH galanga H 111 109 transp--Methoxybenzoicp-Methoxy cinnamic acid acid 109 trans H-p -Methoxy cinnamic acid H H 2Me H OMeK. CH galanga H 2Me COOH K. CH galanga 110 p-Hydroxybenzoic acid 110 p-109Hydroxybenzoic H trans -acidp-Methoxy cinnamic OH acid H COOH H OH H 2Me COOH K. CH galanga [13,50] 112110 p-Hydroxybenzoic Vanillic acid acid 110 Hp-Hydroxybenzoic acid OMe OH H OHCOOH OH COOH COOH 111 p-Methoxybenzoic acid 111 p-110Methoxybenzoic H p- acidHydroxybenzoic acid OMe H COOH H OMe OH COOH COOH[13,50] [13,50] [13,50] 111 p-Methoxybenzoic acid 111 Hp-Methoxybenzoic acid OMe H COOH OMe COOH [13,50] 113 Methyl 3,4-dihydroxybenzoate OH OH COOMe [13,50] 112 Vanillic acid 112 111 OMeVanillic p-acidMethoxybenzoic acid OH OMe H COOH OH OMe COOH COOH 112 Vanillic acid 112 OMe Vanillic acid OH OMe COOH OH COOH 112 Vanillic acid OMe OH COOH

Nutrients 2019, 11, 2396 24 of 38 Nutrients 2019, 11, 2396 24 of 38

113 Methyl 3,4-dihydroxybenzoate OH OH COOMe 113 Methyl 3,4-dihydroxybenzoate OH OH COOMe Nutrients 2019, 11, 2396 Methyl (2R,3S)-2,3-dihydroxy-3-(4- 19 of 33 114 Methyl (2R,3S)-2,3-dihydroxy-3-(4- Me - - 114 methoxyphenyl) propanoate Me - - methoxyphenyl) propanoate Ethyl-(2R,3S)-2,3-dihydroxy-3-(4- 115 Ethyl-(2R,3S)-2,3-dihydroxy-3-(4- 2Me CH - - 115 methoxyphenyl) propanoate 2Me CH - - methoxyphenyl) propanoateTable 2. Cont.

R,3(1R,5R)-1,5-Epoxy-3-hydroxy-1-(3,4- No NameR,3(1R,5R)-1,5-Epoxy-3-hydroxy-1-(3,4- R R R R Plant Ref 116 dihydroxyphenyl)-7-(3,4-dihydroxy phenyl)1 H2 3 - 4 - dihydroxyphenyl)-7-(3,4-dihydroxy phenyl) H - - 116 heptane 114 Methyl (2R,3S)-2,3-dihydroxy-3-(4-methoxyphenyl) propanoateheptane Me - - [13] [13] 115 Ethyl-(2R,3S)-2,3-dihydroxy-3-(4-methoxyphenyl) propanoate CH2Me - - R,3(1R,5R)-1,5-Epoxy-3-hydroxy-1-(3,4- R,3(1R,5R)-1,5-Epoxy-3-hydroxy-1-(3,4- 116 (1R,3R,5R)-1,5-Epoxy-3-hydroxy-1-(3,4-dihydroxyphenyl)-7-(3,4-dihydroxy117 dihydroxyphenyl)-7-(4-hydroxyphenyl) phenyl) heptane H-- D-glc - - 117 dihydroxyphenyl)-7-(4-hydroxyphenyl) D-glc - - (1R,3R,5R)-1,5-Epoxy-3-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)heptane heptane3-O- [13] 117 heptane 3-O-β-D-glucopyranosideD-glc - - 3-O-β-D-glucopyranoside β-D-glucopyranoside 118 ‘-hydroxy-42 ‘,6‘-dimethoxychalcone H - K. parviflora - 118 2‘-hydroxy-4‘,6‘-dimethoxychalcone118 ‘-hydroxy-42 ‘,6‘-dimethoxychalcone H H - - - K. parviflora - [24,71] K. angustifoliaK. parviflora [24,71] 119 ‘-hydroxy-4,42 ‘,6‘-trimethoxychalcone Me - - K. angustifolia [24,71] 119 2‘-hydroxy-4,4‘,6‘-trimethoxychalcone119 ‘-hydroxy-4,42 ‘,6‘-trimethoxychalcone Me Me -- - - K. angustifolia No Name Structure Plant Ref No Name No Name Structure Structure Plant Plant Ref Ref

120 Desmethoxyyangonin 120 Desmethoxyyangonin 120 Desmethoxyyangonin

K. marginata [36] K. marginata [36] K. marginata [36]

121 Bisdemethoxycurcumin 121 Bisdemethoxycurcumin 121 Bisdemethoxycurcumin Nutrients 2019, 11, 2396 25 of 38 Nutrients 2019, 11, 2396 25 of 38

1-(4-Hydroxy-3-methoxyphenyl)-7- 122 1-(4-Hydroxy-3-methoxyphenyl)-7- K. galanga 122 1-(4-Hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)heptane-1,2,3,5,6-pentaol122 (4-hydroxyphenyl)heptane-1,2,3,5,6-pentaol K. galanga K. galanga (4-hydroxyphenyl)heptane-1,2,3,5,6-pentaol

[13]

R,5S)-3,5-Dihydroxy-1-(3,4- R,5(3S)-3,5-Dihydroxy-1-(3,4- dihydroxyphenyl)-7-(4-hydroxy(3 phenyl) 123 (3R,5S)-3,5-Dihydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxy123 phenyl)dihydroxyphenyl)-7-(4-hydroxy heptane phenyl) 123 heptane heptane K. galanga

[13] [13]

124 Phaeoheptanoxide 124 Phaeoheptanoxide K. galanga K. galanga

125 Hedycoropyran B 125 Hedycoropyran B

Nutrients 2019, 11, 2396 25 of 38 Nutrients 2019, 11, 2396 25 of 38

1-(4-Hydroxy-3-methoxyphenyl)-7- 122 1-(4-Hydroxy-3-methoxyphenyl)-7- K. galanga 122 (4-hydroxyphenyl)heptane-1,2,3,5,6-pentaol K. galanga (4-hydroxyphenyl)heptane-1,2,3,5,6-pentaol

Nutrients 2019, 11, 2396 20 of 33 R,5(3S)-3,5-Dihydroxy-1-(3,4- R,5(3S)-3,5-Dihydroxy-1-(3,4- 123 dihydroxyphenyl)-7-(4-hydroxy phenyl) 123 dihydroxyphenyl)-7-(4-hydroxy phenyl) heptane heptane

Table 2. Cont. [13] [13] No Name Structure Plant Ref

124 Phaeoheptanoxide 124 Phaeoheptanoxide Phaeoheptanoxide K. galanga 124 K. galanga

125 Hedycoropyran B 125 Hedycoropyran B 125 Hedycoropyran B

Nutrients 2019, 11, 2396 26 of 38 Nutrients 2019, 11, 2396 26 of 38

O-4- 1-O-4-Carbonxylphenyl-(6-O-4- 126 1-O-4-Carbonxylphenyl-(6-O-4- 126 hydroxybenzoyl)- 126 1-O-4-Carbonxylphenyl-(6-O-4-hydroxybenzoyl)-β-D-glucopyranoside126 hydroxybenzoyl)- β-D-glucopyranoside hydroxybenzoyl)- β-D-glucopyranoside

127 Dihydro-5,6-dehydrokawain 127 Dihydro-5,6-dehydrokawain 127 Dihydro-5,6-dehydrokawain K. parviflora [13,50]

K. parviflora [13,50] 128 R=OH; (-)-Hydroxypanduratin A 128 R=OH; (-)-Hydroxypanduratin A K. parviflora [13,50] 128 R=OH; (-)-Hydroxypanduratin A K. parviflora [13,50]

129, R=OMe; (-)-Panduratin A 129, R=OMe; (-)-Panduratin A 129, R=OMe; (-)-Panduratin A

130 Cinnamaldehyde K. galanga [78] 130 Cinnamaldehyde K. galanga [78]

131 R=Me; Crotepoxide K. angustifolia [24,33] 131 R=Me; Crotepoxide K. angustifolia [24,33]

Nutrients 2019, 11, 2396 26 of 38

1-O-4-Carbonxylphenyl-(6-O-4- 126 hydroxybenzoyl)- β-D-glucopyranoside

127 Dihydro-5,6-dehydrokawain

128 R=OH; (-)-Hydroxypanduratin A K. parviflora [13,50] Nutrients 2019, 11, 2396 21 of 33

129, R=OMe; (-)-Panduratin A

Table 2. Cont.

No Name Structure Plant Ref

Nutrients 2019, 11, 2396 27 of 38 130 Cinnamaldehyde Nutrients130 2019, 11, 2396 Cinnamaldehyde K. galanga K. galanga [78][78]27 of 38

131 R=Me; Crotepoxide 131 R=Me; Crotepoxide K. angustifolia [24,33] K. angustifolia [24,33]

132 R=Benzen; Boesenboxide

132 R=Benzen; Boesenboxide 132 R=Benzen; Boesenboxide

R=H; Zeylenol 133 R=H; Zeylenol 133 134 R=Me; 6-methylzeylenol 134133 R=Me; R=H; 6-methylzeylenol Zeylenol 134 R=Me; 6-methylzeylenol

rel-(5aS,10bS)-5a,10b-Dihydro-1,3,5a,9- rel-(5aS,10bS)-5a,10b-Dihydro-1,3,5a,9-tetrahydroxy-8-methoxy-6H-benz[tetrahydroxy-8-methoxy-6b]indeno[1–rel-(5aS,10bS)-5a,10b-Dihydro-1,3,5a,9-d]furan-6-one 135 tetrahydroxy-8-methoxy-6H-benz[b]indeno[1– 5a-O-[α-l-rhamnopyranosyl-(1 6)-β-d-glucopyranoside]135 K. parvifloraK. parviflora [79][ 79] 135 tetrahydroxy-8-methoxy-6H-benz[b]indeno[1– K. parviflora [79] → d]furan-6-one O5a--[α-L-rhamnopyranosyl-(1→ 135 d]furan-6-one O5a--[α-L-rhamnopyranosyl-(1 K. parviflora [79] d]furan-6-one O5a--[α-L-rhamnopyranosyl-(1→ 6)-β-D-glucopyranoside] 6)-β-D-glucopyranoside]

R= R=α-L-rha-(1α-L-rha-(1→6)-6)-β-D-glcβ-D-glc →R= α-L-rha-(1 →6)-β-D-glc

Nutrients 2019, 11, 2396 22 of 33

Nutrients 2019, 11, 2396 28 of 38 Table 2. Cont. Nutrients 2019, 11, 2396 28 of 38 No Name Structure Plant Ref

rel-(5aS,10bR)-5a,10b-Dihydro-1,3,5a,9-

tetrahydroxy-8-methoxy-6H-benz[b]indeno[1– 136 rel-(5aS,10bR)-5a,10b-Dihydro-1,3,5a,9- rel-(5aS,10bR)-5a,10b-Dihydro-1,3,5a,9-tetrahydroxy-8-methoxy-6H-benz[d]furan-6-oneb]indeno[1– Od5a--[]furan-6-oneα-L-rhamnopyranosyl-(1→ 136 tetrahydroxy-8-methoxy-6 5a-O-[α-l-rhamnopyranosyl-(1 6)-β-d-glucopyranoside] H-benz[b]indeno[1– → 136 6)-β-D-glucopyranoside] d]furan-6-one O5a--[α-L-rhamnopyranosyl-(1→

6)-β-D-glucopyranoside] R= α-L-rha-(1→6)-β-D-glc

R=α-L-rha-(1 R=6)-β-D-glc α-L-rha-(1→6)-β-D-glc

R,3S,4S)-3-O-[α-L-Rhamnopyranosyl-(1 → 6)- (2 β-D-glucopyranosyl]-3O-methyl-′- ent- R,3S,4S)-3-O-[α-L-Rhamnopyranosyl-(1 → 6)- (2R,3S,4S)-3-O-[α-l-Rhamnopyranosyl-(1epicatechin-(2 → → → → (2 α O 3,4α 4)-(5aS,10bS)- 6)-β-d-glucopyranosyl]-30-O-methyl-ent-epicatechin-(2α O 3,4β-Dα-glucopyranosyl]-3O-methyl-′- ent- 137 1375a,10b-dihydro-1,3,5a,9-tetrahydroxy-8- → → → 4)-(5aS,10bS)-5a,10b-dihydro-1,3,5a,9-tetrahydroxy-8-methoxy-6Hepicatechin-(2-benz[b]indeno[1,2-d]furan-6-one methoxy-6 α→O→3,4α→ 4)-(5aS,10bS)- 5a-O-[α-l-rhamnopyranosyl-(1 6)-β-d-glucopyranoside] H-benz[b]indeno[1,2-d]furan-6-one → 1375a,10b-dihydro-1,3,5a,9-tetrahydroxy-8- 5a- → methoxy-6 O-[α-L-rhamnopyranosyl-(1 6)-β-D- -benz[]indeno[1,2-]furan-6-one glucopyranoside]H b d 5a- O-[α-L-rhamnopyranosyl-(1→ 6)-β-D- glucopyranoside]

R= R=α-L-rha-(1 6)-β-D-glc α-L-rha-(1→6)-β-D-glc R=

α-L-rha-(1→6)-β-D-glc

Nutrients 2019, 11, 2396 23 of 33 Nutrients 2019, 11, 2396 29 of 38

Nutrients 2019, 11, 2396 29 of 38 Nutrients 2019, 11, 2396 TableTable 3.3. SteroidSteroid and triterpenes. triterpenes. 29 of 38 Table 3. Steroid and triterpenes. Table 3. Steroid and triterpenes.

138–139 138–139

No Name Structure Plant Ref No Name Structure138–139 Plant Ref 138 β-Sitosterol 138–139 R=H No 138 Nameβ-Sitosterol R=H Structure Plant Ref No 139 β-Sitosterol-Nameβ-D-glucoside β-D-glc StructureR= Plant Ref 138 β-Sitosterol R=H 138 139 β-Sitosterolβ-Sitosterol- β-D-glucoside R=β-D-glc R=H 139 β-Sitosterol-β-D-glucoside β-D-glc R= 139 β-Sitosterol-β-D-glucoside β-D-glc R= K.marginata K.marginata [24,33,36] K. angustifolia [24,33,36] 140 Stigmasterol K. angustifoliaK.marginata K.K.marginata angustifolia [24,33,36] [24,33,36] 140 140Stigmasterol Stigmasterol K. angustifolia 140 Stigmasterol

141 S)-24-methyl-lanosta-9(11),(24 25-dien-3β-ol K. angustifolia [24]

141 S)-24-methyl-lanosta-9(11),(24 (24S)-24-methyl-lanosta-9(11), 25-dien-3β-ol K. angustifolia [24] 141 141 S)-24-methyl-lanosta-9(11),(24 25-dien-3β-ol K. angustifoliaK. angustifolia [24][24 ] 25-dien-3β-ol

Nutrients 2019, 11, 2396 24 of 33

Nutrients 2019, 11, 2396 30 of 38 6.1. Diterpenoids 6.1.Kaempferia Diterpenoidsplants were characterized with a predominance of diterpenoids, especially the isopimaranesKaempferia in addition plants were to abietane, characterized labdane, with and a clerodane predominance types of (Table diterpenoids,1). especially the isopimaranes in addition to abietane, labdane, and clerodane types (Table 1). 6.1.1. Isopimarane-Type Diterpenoids 6.1.1. Isopimarane-Type Diterpenoids The isopimaranes reported from the Kaempheria species (Table1) are characterized with the presenceThe of twoisopimaranes double bonds; reported one from is mostly the Kaempheria∆15(16), while species the other (Table is 1) between are characterized∆8(9) or ∆8(14) with[4 ,25the,74 ]. Frompresence the rhizomes of two double of K. galangabonds; ,one 12 usualis mostly isopimarenes ∆15(16), while ( 1–8the ,other10, 11 is, between14, and 17∆8(9)) were or ∆8(14) observed [4,25,74]. that containedFrom the a rhizomes∆8(14),15 motif of K. galanga in addition, 12 usual to the isopimarenes rarely reported (1–8, oxygenated10, 11, 14, and seco-isopimarane 17) were observed (56 that)[16 ]. Fromcontained the rhizomes a ∆8(14),15 ofmotifK. marginatain addition, fiveto the isopimarenes rarely reported with oxygenated a ∆8(14),15 seco-isopimaranemotif were observed (56) [16]. (1 , 2, 8(14),15 52–From54)[36 the]. rhizomes Only one of thumbingK. marginata, isopimarenes, five isopimarenes roscorane with a ∆ A (57 ),motif was were reported observed from (1,K. 2, roscoeana52–54) , which[36]. was Only characterized one thumbing by isopimarenes, only one double roscorane bond ∆A8(9) (57and), was (7-8)-epoxy, reported from as well K. roscoeana as the absence, which was ofthe characterized by only one double bond ∆8(9) and (7-8)-epoxy, as well as the absence of the exomethylene ∆15(16) [26]. exomethylene ∆15(16) [26]. Biosynthesis of Isopimarane-Type Diterpenoids Biosynthesis of Isopimarane-Type Diterpenoids Isopimarane diterpenoids are the most characteristic compounds for Kaempheria plants. Isopimarane diterpenoids are the most characteristic compounds for Kaempheria plants. (E,E,E)- (E,E,E)-Geranylgeranyl diphosphate (GGPP) is a well-known biosynthesized intermediate of Geranylgeranyl diphosphate (GGPP) is a well-known biosynthesized intermediate of diterpenoids as diterpenoids as described by [80]. GGPP is firstly cyclized via copalyl diphosphate (CPP) synthases described by [80]. GGPP is firstly cyclized via copalyl diphosphate (CPP) synthases (CPS), and then (CPS),by the and unknown then by enzyme the unknown (PS), affording enzyme a (PS), charged affording intermediate a charged (INM). intermediate Then, this (INM).intermediate Then, is this intermediatecompletely iscyclized completely by the cyclized enzymatic by the reactions enzymatic via reactionsthe bifunctional via the bifunctional(iso) pimaradiene (iso) pimaradienesynthases synthases(AoCPS-PS, (AoCPS-PS, NfCPS-PS, NfCPS-PS, and AfCPS-PS) and AfCPS-PS) (Scheme 1), (Scheme as described1), as by described Xu et al. by [81]. Xu et al. [81].

SchemeScheme 1. Plausible1. Plausible isopimaradiene isopimaradiene biosynthesis biosynthesis [81] starting [81] withstarting (E,E ,withE)-geranylgeranyl (E,E,E)-geranylgeranyl diphosphate (GGPP):diphosphate (E,E,E)-geranylgeranyl (GGPP): (E,E,E diphosphate;)-geranylgeranyl CPS: diphosphate; copalyl diphosphate CPS: copalyl (CPP) synthases;diphosphate PS: Unknown(CPP) enzyme;synthases; AoCPS-PS, PS: Unknown NfCPS-PS, enzyme; and AfCPS-PS: AoCPS-PS, bifunctional NfCPS-PS, (iso) and pimaradiene AfCPS-PS: synthases. bifunctional (iso) pimaradiene synthases. 6.1.2. Abietane-Type Diterpenoids 6.1.2. Abietane-Type Diterpenoids Seven abietanes (58–64) (Table1) have been isolated and characterized from the rhizomes of K. roscoeanaSeven, and abietanes one (65 (58–64) was) isolated(Table 1) andhave characterized been isolated fromand characterizedK. angustifolia from[26 ,the33,34 rhizomes]. These of highly K. oxygenatedroscoeana, and metabolites one (65) containwas isolated one or and more characterized double bonds from and K. anangustifolia absence [26,33,34]. of exomethylenes, These highly except foroxygenated roscotane D metabolites (61), which contain contains one no or doublemore double bonds. bonds and an absence of exomethylenes, except for roscotane D (61), which contains no double bonds. 6.1.3. Labdane and Clerodane Diterpenoids 6.1.3. Labdane and Clerodane Diterpenoids After isopimarenes, labdane and clerodane represent major diterpenoid classes from the KaempheriaAfterspecies. isopimarenes, Nineteen labdane highly and oxygenatedclerodane represent labdanes major and diterpenoid clerodanes classes (66–86 )from have the been reportedKaempheria from species.Kaempheria Nineteenrhizomes highly oxygenated (Table1)[ labdanes18,26]. and clerodanes From these (66– isolated86) have been labdanes, reported only

Nutrients 2019, 11, 2396 25 of 33

(12Z,14R)-labda-8(17),12-dien-14,15,16-triol (66) has been isolated from K. roscoeana rhizomes. In contrast, several labdane and clerodane types of diterpenoids have been isolated from K. elegans and K. pulchra rhizomes collected in Thailand.

6.1.4. Flavonoids Kaempheria species are characterized by rich biological activity due in part to the presence of a diversity of flavonoids (86–105) and phenolic compounds (106–137) (Table2). K. parviflora rhizomes with flavonoid nuclei contain methoxy groups in specific positions (86–97)[9,55]. Pyrano-flavone, 2”,2”-dimethylpyrano-[5”,6”:8,7]-flavone (105), has been isolated from K. pulchra rhizomes collected from Thailand [18], and flavanones (97–99) have been isolated and identified from K. parviflora rhizomes [70,71]. K. galanga contains kaempferol and kaempferide (98, 99)[78].

6.1.5. Phenolic Compounds From K. galanga rhizomes, diarylheptanoid compounds (116, 117, 122–125) are reported by Yao, Huang, Wang, and He [13]. From K. marginata rhizomes, curcuminoid (121) was characterized by Kaewkroek, Wattanapiromsakul, Kongsaeree, and Tewtrakul [36]. From K. galanga, rhizomes phenolic acids (106–113) were the major compounds isolated, including methoxylated cinnamic acid derivatives. Two (4-methoxyphenyl)-propanoates (114–115) were also isolated from the K. galanga rhizomes [13,50]. S- and R-isomers at C-4 of phenolic glycosides (135 and 136) as well as a rare phenolic glycoside (137) were observed in K. previflora rhizomes [79]. All the phenolic compounds (106–137) are summarized in Table2.

6.1.6. Steroids and Triterpenes Steroids represent a minor class of compounds reported from Kaempheria species. Only three steroids, β-sitosterol (138), β-sitosterol-β-D-glucoside (139), and stigmasterol (140) (Table3) have been reported from K. marginata rhizomes [36]. Moreover, only one lanostane type triterpene, (24S)-24-methyl-lanosta-9(11), 25-dien-3β-ol (141), was isolated from K. angustifolia [24].

6.1.7. Volatile Oils Kaempheria species were documented as very rich plants with volatile oils such as K. galanga [29,73,82,83], K. angustiflora [29], and K. marginata [29]. The volatile oil of K. galanga has been reported as a potential market product in India and over all the world with market values around 600–700 US$/kg on the international market [83]. Phenylpropanoids and/or cinamates were represented as major constituents of volatile oils derived from Kaempheria species followed by monoterpenes [29,73,82]. The phenylpropanoid compound, trans-ethyl cinnamate, was documented as a principal component of volatile oils of all the studied Kaempheria species up to date with concentrations varied from 16–35% of the total identified [29,73,82,83]. The volatile oils of Kaempheria species were reported to have numerous biological activities such as anti-microbial [83], antioxidant [35], nutraceutical [83], nematicidal toxicity [82], and larvicide activities [29]. Table4 summarized the main components (142–157) of the reported volatile oils of Kaempheria species. Nutrients 2019, 11, 2396 26 of 33

Table 4. Main components of volatile oils of Kaempferia species.

No Name Plant Ref 142 δ-3-Carene 143 E-Ethyl cinnamate 144 Ethyl-p-methoxycinnamate 145 γ-Cadinene 146 1,8-Cineole 147 Trans-cinnamaldehyde 148 Borneol K. galanga [29,35,82,83] 149 Pentadecane 150 γ-car-3-ene 151 Linoleoyl chloride 152 Caryophyllene oxide 153 Cubenol 154 Caryophyllene 155 Limonene 156 Camphene 157 α-Pinene

7. Principal Components Analysis (PCA) and Agglomerative Hierarchical Clustering (AHC) for Kaempferia Species To assess the correlation between the various Kaempferia species, chemical classes of different compounds were subjected to PCA and AHC (Figure3). According to the similarity, the analysis showed that we can group the Kaempferia species under three groups: the first group comprised K. galanga, K. marginata, K. pulchra, and K. roscoeana, and these species are correlated to isopimaranes compounds. The Pearson correlation coefficient (r) between K. marginata and K. pulchra was the highest with r = 0.938, while between K. marginata and K. roscoeana, it was 0.771, between K. roscoeana and K. pulchra, it was 0.766, and between K. marginata and K. galanga, it was 0.615 (Table5).

Table 5. Proximity matrix (Pearson correlation coefficient) of the seven Kaempferia species based on the chemical classes reported.

K. angustifolia K. elegans K. galanga K. marginata K. parviflora K. pulchra K. elegans 0.539 − K. galanga 0.042 0.339 − − K. marginata 0.500 0.241 0.615 − − K. parviflora 0.833 0.312 0.075 0.280 − − K. pulchra 0.675 0.053 0.378 0.938 0.372 − − K. roscoeana 0.643 0.225 0.206 0.771 0.513 0.766 − − −

The second group contained K. angustifolia and K. parviflora (r = 0.833), and this group showed a close correlation to flavonoids and phenolics. However, the K. elegans was separated alone, and showed a close relation to labdane and clerodane compounds. The similarities within each group might be ascribed to the genetic relations, as well as the environmental and microclimatic conditions [1–3]. In a study of a genetic variation of Kaempferia species based on chloroplast DNA [5], K. marginata and K. galanga were grouped together, which is agreeable with our results (r = 0.615) according to the PCA data of the present study based on the chemical composition. However, in contrast to the data from the PCA, K. angustifolia and K. parviflora were separated in different groups, but K. elegans and Nutrients 2019, 11, 2396 27 of 33

K. parviflora were grouped together. In another recent study, based on the DNA and morphological characteristics [84], K. angustifolia and K. parviflora were grouped together in agreement with the chemicalNutrients variation2019, 11, 2396 of the present study. 33 of 38

Figure 3. (A) Agglomerative hierarchical clustering (AHC) and (B) Principal component analysis (PCA)Figure based 3. (A on) Agglomerative the chemical compositionhierarchical clustering of different (AHC) chemical and ( classesB) Principal of seven componentKaempferia analysisspecies (K.(PCA) angustifolia based, onK. the elegans chemical, K. galanga composition, K. marginata of different, K.parviflora chemical, classesK. pulchra of seven, and KaempferiaK. roscoeana species). (K. angustifolia, K. elegans, K. galanga, K. marginata, K. parviflora, K. pulchra, and K. roscoeana). 8. Conclusions 8. Conclusions Kaempheria species are widely used plants in traditional medicine worldwide. All the biological activityKaempheria data for thesespecies plants are widely and theirused plants isolated in tradit constituentsional medicine haveresulted worldwide. in numerousAll the biological leads for medicinalactivity data drugs. for Mainly,these plants seven an rhizomesd their isolated of Kaempheria constituentsplants have afforded resulted a vast in numerous array of diterpenoids, leads for especiallymedicinal the drugs. isopimarane Mainly, seven type, rhizomes along with of Kaempheria significant plants bioactive afforded methoxylated a vast array flavonoids. of diterpenoids, From all especially the isopimarane type, along with significant bioactive methoxylated flavonoids. From all these documented chemical and biological results, these plants have been and continue to be a promising source for medicinal natural products and food industrial products.

Nutrients 2019, 11, 2396 28 of 33 these documented chemical and biological results, these plants have been and continue to be a promising source for medicinal natural products and food industrial products.

Author Contributions: A.I.E., T.A.M. and M.-E.F.H. suggested and designed the study. A.I.E., T.A.M., A.F.E., and A.M.A.-E.G. did the data preparation and structure drawing. A.I.E., T.A.M., A.M.A.-E.G., and M.-E.F.H. collected the data. A.S.A., A.A.S., T.Y., A.R.H.F., and M.N. wrote the original manuscript. A.I.E., T.A.M., M.-E.F.H., P.W.P., A.U., A.S.A., A.A.S., and H.R.E.-S. edited the final manuscript. All the authors reviewed and approved the manuscript. Funding: This research received no external funding. Acknowledgments: The authors are thankful to the Deanship of the Scientific Research and Research Center, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Elshamy gratefully acknowledges the Takeda Science Foundation, Japan for financial support. Prof. Mohamed Hegazy gratefully acknowledges the financial support from Alexander von Humboldt Foundation “Georg Foster Research Fellowship for Experienced Researcher”. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

K. Kaempheria Sp. Species PCA Principal component analysis AHC Agglomerative hierarchical clustering CCA Significant Cholangiocarcinoma HSC-2 Mouth squamous cell carcinoma EAC Ehrlich ascites carcinoma cancer cells HL-60 Human leukemia cancer cells CL-6 Human cholangiocarcinoma cells TKI Tyrosine kinase inhibitors BCRP Breast cancer resistance protein MTT (3-[4,5,[4,5-Dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) assay CH2Cl2 Dichloromethane BChE Butyrylcholinesterase NO Nitric oxide CUPRAC Modified cupric reducing antioxidant capacity PDE5 Phosphodiesterase type 5 inhibitor AP Aerial parts AChE Acetylcholinesterase RBL-2H3 Rat Basophilic Leukemia cells P38 Type of mitogen-activated protein kinases STAT1 and 3 Signal transducers and activators of transcription 1 and 3 MeOH Methanol EtOAc Ethyl acetate MCF-7 Breast cancer cells HT-29 Colorectal adenocarcinoma cell PMF Polymethoxyflavonoid-rich fraction TSOD Tsumura Suzuki obese diabetes GGPP (E,E,E)-Geranylgeranyl diphosphate CPP Copalyl diphosphate CPS Copalyl diphosphate synthases EtOH Ethanol AChE Acetylcholinesterase ABTS 2,20-Azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) assay Vpr Viral protein R DPPH 1,1-Diphenyl-2-picrylhydrazyl assay FRAP Ferric reducing antioxidant power Nutrients 2019, 11, 2396 29 of 33

CYP3A Cytochrome P450, family 3, subfamily A NF-κB Nuclear factor pathway Rh Rhizomes BChE Butyrylcholinesterase STZ Streptozotocin MPO myeloperoxidase DMF Dimethylformamide MAPKs Type of mitogen-activated protein kinases PGE2 Prostaglandin E2

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