Melanogenesis-Inhibitory and Cytotoxic Activities of Diarylheptanoids from Acer nikoense Bark and Their Derivatives

Nine cyclic diarylheptanoids, 1-9, including two new compounds, i.e., 9-oxoacerogenin A (8) and 9-O-β-D-glucopyranosylacerogenin K (9), along with three acyclic diarylheptanoids, 10-12, and four phenolic compounds, 13-16, were isolated from a MeOH extract of the bark of Acer nikoense (Aceraceae). Acid hydrolysis of 9 yielded acerogenin K (17) and D-glucose. Two of the cyclic diarylheptanoids, acerogenin A (1) and (R)-acerogenin B (5), were converted to their ether and ester derivatives, 18-24 and 27-33, respectively, and to the dehydrated derivatives, 25, 26, 34, and 35. Upon evaluation of compounds 1-16 and 18-35 for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α-melanocyte-stimulating hormone (α-MSH), eight natural glycosides, i.e., six diarylheptanoid glycosides, 2-4, 6, 9, and 12, and two phenolic glycosides, 15 and 16, exhibited inhibitory activities with 24-61% reduction of melanin content at 100?μM concentration with no or almost no toxicity to the cells (88-106% of cell viability at 100?μM). In addition, when compounds 1-16 and 18-35 were evaluated for cytotoxic activity against human cancer cell lines, two natural acyclic diarylheptanoids, 10 and 11, ten ether and ester derivatives, 18-22 and 27-31, and two dehydrated derivatives, 34 and 35, exhibited potent cytotoxicities against HL60 human leukemia cell line (IC(50) 8.1-19.3?μM), and five compounds, 10, 11, 20, 29, and 30, against CRL1579 human melanoma cell line (IC(50) 10.1-18.4?μM).     

Platelet-activating factor (PAF) receptor binding antagonists from Alpinia officinarum

The bioassay-guided purification of ether extracts of Alpinia officinarum led to the isolation of two new compounds 6-hydroxy-1,7-diphenyl-4-en-3-heptanone (1) and 6-(2-hydroxy-phenyl)-4-methoxy-2-pyrone (4) as well as three known compounds 1,7-diphenyl-4-en-3-heptanone (2), 1,7-diphenyl-5-methoxy-3-heptanone (3), and apigenin (5). Their structures were established on the basis of spectral methods. All three diarylheptanoids 1, 2, and 3 exhibited potent PAF receptor binding inhibitory activities with an IC₅₀ of 1.3, 5.0, and 1.6 μM, respectively. These studies have identified diarylheptanoids as a novel class of potent PAF antagonists.     

Melanogenesis‐Inhibitory and Cytotoxic Activities of Diarylheptanoids from Acer nikoense Bark and Their Derivatives

Nine cyclic diarylheptanoids, 1 – 9 , including two new compounds, i.e., 9‐oxoacerogenin A ( 8 ) and 9‐O‐β‐D ‐glucopyranosylacerogenin K ( 9 ), along with three acyclic diarylheptanoids, 10 – 12 , and four phenolic compounds, 13 – 16 , were isolated from a MeOH extract of the bark of Acer nikoense (Aceraceae). Acid hydrolysis of 9 yielded acerogenin K ( 17 ) and D ‐glucose. Two of the cyclic diarylheptanoids, acerogenin A ( 1 ) and (R)‐acerogenin B ( 5 ), were converted to their ether and ester derivatives, 18 – 24 and 27 – 33 , respectively, and to the dehydrated derivatives, 25, 26, 34 , and 35 . Upon evaluation of compounds 1 – 16 and 18 – 35 for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α‐melanocyte‐stimulating hormone (α‐MSH), eight natural glycosides, i.e., six diarylheptanoid glycosides, 2 – 4, 6, 9 , and 12 , and two phenolic glycosides, 15 and 16 , exhibited inhibitory activities with 24–61% reduction of melanin content at 100 μM concentration with no or almost no toxicity to the cells (88–106% of cell viability at 100 μM ). In addition, when compounds 1 – 16 and 18 – 35 were evaluated for cytotoxic activity against human cancer cell lines, two natural acyclic diarylheptanoids, 10 and 11 , ten ether and ester derivatives, 18 – 22 and 27 – 31 , and two dehydrated derivatives, 34 and 35 , exhibited potent cytotoxicities against HL60 human leukemia cell line (IC₅₀ 8.1–19.3 μM ), and five compounds, 10, 11, 20, 29 , and 30 , against CRL1579 human melanoma cell line (IC₅₀ 10.1–18.4 μM ).     

Structure-antiemetic-activity of some diarylheptanoids and their analogues

The structure-activity relationship of diarylheptanoids and their analogues inhibitory of emesis induced by copper sulfate in young chicks was investigated by testing 19 compounds. The compounds are 5 diarylheptanoids isolated from Alpinia katsumadai (Zingiberacea), 5 chemical derivatives of them, 6 analogues isolated from Zingiber officinale rhizome (Zingiberaceae), and 3 analogues available on the market. Among them, two types of essential functional structure of diarylheptanoids and their analogues showed the inhibitory effects against emesis.     

Chemopreventive potential of cyclic diarylheptanoids

Eleven cyclic diarylheptanoids and seven related compounds were screened as potential antitumor promoters by using the in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen (EBV-EA) activation assay. In addition, the cyclic diarylheptanoid myricanone (2) was examined for antitumor initiating activity in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite as an initiator and TPA as a promoter. Myricanone (2) exhibited significant antitumor-initiating effect on mouse skin. These data suggest that cyclic, as well as linear, diarylheptanoids might be valuable chemopreventors.     

Compounds of Alpinia katsumadai as potential efflux inhibitors in Mycobacterium smegmatis

Efflux pumps are one of the well established mechanisms that contribute to antibiotic resistance in bacteria, such as mycobacteria. As a result, the identification of efflux pump inhibitors is an attractive target in antimicrobial therapy. The isolated compounds, three diarylheptanoids, trans,trans-1,7-diphenylhepta-4,6-dien-3-one (1), (5R)-trans-1,7-diphenyl-5-hydroxyhept-6-en-3-one (2), (3S,5S)-trans-1,7-diphenylhept-1-ene-3,5-diol (3) and the flavonoid pinocembrin (4), from Alpinia katsumadai, Zingiberaceae, were examined for their antimycobacterial activity and their synergistic effects with different antibiotics against M. smegmatis mc(2) 155. Furthermore, these compounds were evaluated as potential EtBr efflux inhibitors. Although they showed weak antimycobacterial activities (MIC ≥ 64 mg/L), especially compound 1 revealed a significant activity on the EtBr accumulation and efflux as well as a synergistic effect in combination with rifampicin.     

Studies on the effectiveness of diarylheptanoids derivatives against Leishmania amazonensis

In a previous work we demonstrated that diarylheptanoids extracted from Centrolobium sclerophyllum are very active against Leishmania amazonensis promastigotes. In order to continue our studies with these class of compounds, we decided to evaluate the activity of several diarylheptanoids derived from curcumin (diferuloyl methane) against the extracellular form (promastigotes) of L. amazonensis. Furthermore, an experiment against the intracellular form of the parasite (amastigotes) was carried out, comparing the most active compound among the curcumin derivatives (the methylcurcumin) with des-O-methylcentrolobine, the most active diarylheptanoid derived from C. sclerophyllum.     

Diarylheptanoids from Myrica arborea

Investigations of the stem and root bark of Myrica arborea (Myricaceae) have yielded two novel diarylheptanoids, myricarborin and 11-O-beta-D-xylopyranosylmyricanol along with the known myricanol and 5-O-beta-D-glucopyranosylmyricanol. The structures of the novel compounds were determined by spectroscopic methods.     

Diarylheptanoids from Curcuma kwangsiensis and their inhibitory activity on nitric oxide production in lipopolysaccharide-activated macrophages

Eleven diarylheptanoids (1-11) were isolated from rhizomes of Curcuma kwangsiensis, together with seven known compounds. Their structures were elucidated by 1D and 2D NMR, circular dichroism (CD), and accurate mass measurements. Inhibitory effects of the isolated compounds on nitric oxide production in lipopolysaccaride-activated macrophages were evaluated. Compounds 1, 2, and 3 showed strong inhibitory activity on NO production with IC(50) values of 3.13, 2.81 and 2.41 μM, respectively.     

Antioxidant properties of gingerol related compounds from ginger

Ginger (Zingiber officinale Roscoe) shows an antioxidant activity, and we have been engaging to determine the structures of more than 50 antioxidants isolated from the rhizomes of ginger. The isolated antioxidants are divided into two groups; gingerol related compounds and diarylheptanoids. In this study, structure-activity relationship of gingerol related compounds was evaluated. Gingerol related compounds substituted with an alkyl group bearing 10-, 12- or 14-carbon chain length were isolated from the dichloromethane extract of rhizomes using repeated chromatographic techniques. The antioxidant activities of these compounds were evaluated by the following measurements; 1) 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, 2) inhibitory effect on oxidation of methyl linoleate under aeration and heating by the Oil Stability Index (OSI) method, and 3) inhibitory effect on oxidation of liposome induced by 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH). These results suggested that the substituents on the alkyl chain might contribute to both radical scavenging effect and inhibitory effect of autoxidation of oils, while inhibitory effects against the AAPH-induced peroxidation of liposome was somewhat influenced by the alkyl chain length; the antioxidant activity might be due to not only radical scavenging activity of antioxidants but also their affinity of the antioxidants to the substrates.     

Macrocyclic diarylheptanoids from Garuga pinnata

Three macrocyclic diarylheptanoids, 6'-hydroxygaruganin V (1), 9'-desmethylgarugamblin I (2) and 1,9'-didesmethylgaruganin III (3) were isolated from the petroleum ether and dichloromethane extracts of the stem bark of Garuga pinnata. The structures of these compounds were established by extensive spectroscopic studies, including high field NMR and MS measurements.     

Anti-neuroinflammatory diarylheptanoids from the rhizomes of Dioscorea nipponica

In a continuing search for bioactive constituents from Dioscoreaceae medicinal plants, two new cyclic diarylheptanoids, diosniponol A (1) and B (2), together with 10 known compounds (3–12) were isolated from the rhizomes of Dioscorea nipponica. The structures of these new compounds were determined by spectroscopic analyses, including extensive two-dimensional nuclear magnetic resonance, high-resolution mass spectrometry, and optical rotation. All isolated compounds 1–12 were evaluated for their effects on nitric oxide (NO) production in murine microglia cell line BV-2. Compounds 8 and 11 showed potent inhibitory activities on NO production (IC₅₀ 13.36 and 14.36 μM, respectively) without cell toxicity in lipopolysaccharide-activated BV-2 cells.     

Osteogenic activity of diphenyl ether-type cyclic diarylheptanoids derived from Acer nikoense

Osteogenic activity of six diarylheptanoids, acerogenin A (1), (R)-acerogenin B (2), aceroside I (3), aceroside B₁ (4), aceroside III (5) and (−)-centrolobol (6) and two phenolic compounds; (+)-rhododendrol (7) and (+)-cathechin (8), isolated from the stem bark of Acer nikoense (Nikko maple) was evaluated using alkaline phosphatase (ALP) activity as a marker for early osteoblast differentiation. We found that the diphenyl ether-type cyclic diarylheptanoids 1-5 promoted ALP activity in mouse preosteoblastic MC3T3-E1 cells without affecting cell proliferation, but linear-type diarylheptanoid 6 and phenolic compounds 7 and 8 did not. Diphenyl ether-type cyclic diarylheptanoids 1-4 also increased protein production of osteocalcin, a late stage maker for osteoblast differentiation, and induced osteoblastic mineralization. Structure-activity relationships of these compounds demonstrated that the stimulative efficacy of aglycones was higher than that of its glycosides. Taken together, diphenyl ether-type cyclic diarylheptanoids promote early- and late-stage osteoblastogenesis, which may open the possibility for the development of novel osteogenic agents.     

Inhibitors from the rhizomes of Alpinia officinarum on production of nitric oxide in lipopolysaccharide-activated macrophages and the structural requirements of diarylheptanoids for the activity

The 80% aqueous acetone extract from the rhizomes of Alpinia officinarum, a Chinese medicinal herb, were found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. Through bioassay-guided separation, two diarylheptanoids [7-(4'-hydroxy-3'-methoxyphenyl-1-phenylhept-4-en-3-one and 3,5-dihydroxy-1,7-diphenylheptane] and a flavonol constituent (galangin) substantially inhibited LPS-induced NO production with IC50 values of 33-62 microM. To clarify structure-activity relationships of diarylheptanoids, related diarylheptanoids from Curcuma zedoaria were examined. Results indicate that the double bond or enone moiety at the 1-7 positions is important for the activity.     

Diarylheptanoids,flavonoids and other constituents from two neotropical Renealmia species (Zingiberaceae)

Phytochemical investigations of the neotropical ginger species Renealmia alpinia and Renealmia cernua led to the isolation of two hitherto unknown diarylheptanoids, named renealpin (1) and renecernin (2). Furthermore, five known diarylheptanoids (3–7), one chalcone (9), two flavonoids (10, 11) and [2]-gingerol (8) were isolated. The organ specific accumulation patterns and chemosystematic significance of these compounds are discussed.     

Diarylheptanoids from the rhizomes of Zingiber officinale

Seven new diarylheptanoids, i.e., (3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptane, (3R,5S)-3-acetoxy-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptane, (3R,5S)-3,5-dihydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane, (5S)-5-acetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptan-3-one, 5-hydroxy-1-(3,4-dihydroxy-5-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptan-3-one, 5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(3,4-dihydroxy-5-methoxy-phenyl)heptan-3-one and 1,5-epoxy-3-hydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane were isolated from the rhizomes of Chinese ginger (Zingiber officinale Roscoe), along with 25 known compounds, i.e., 8 diarylheptanoids, 14 gingerol analogs, a diterpene and 2 steroids. Their structures were elucidated by spectroscopic and chemical methods.     

Determination of diarylheptanoids from Alpinia officinarum (Lesser Galangal) by HPLC with photodiode array and electrochemical detection

Normal-phase column chromatography followed by semi-preparative reversed-phase HPLC has been used to isolate, from the rhizomes of Alpinia officinarum, five diarylheptanoids identified as 5-hydroxy-7-(4"-hydroxy-3"-methoxyphenyl)-1-phenyl-3-heptanone, 5-methoxy-7-(4"-hydroxy-3"-methoxyphenyl)-1-phenyl-3-heptanone, 7-(4"-hydroxyphenyl)-1-phenylhept-4-en-3-one, 7-(4"-hydroxy-3"-methoxyphenyl)-1-phenyl-hept-4-en-3-one, 1,7-diphenylhept-4-en-3-one. The levels of these five diarylheptanoids in root material were determined quantitatively by HPLC with UV detection and the assay methods so developed were simple, rapid and accurate. Four of the diarylheptanoids could also be detected by HPLC with electrochemical detection (ECD) in the oxidative mode, and ECD was found to have a higher sensitivity than photodiode array detection.     

Biological evaluation of curcumin and related diarylheptanoids

Nine derivatives of three natural diarylheptanoids, curcumin, demethoxycurcumin and bisdemethoxycurcumin, were prepared. Their antioxidant, free radical scavenging, nitric oxide (NO) inhibitory and cytotoxic activities were evaluated and compared with those of the respective natural compounds. Curcumin (1), demethoxycurcumin (2), demethyldemethoxy-curcumin (C3), diacetyldemethoxycurcumin (AC2) and triacetyldemethylcurcumin (AC5) exhibited higher antioxidant activity than quercetin while products from demethylation of 1 and 2 exhibited higher free radical scavenging activity. Compounds AC2 and AC5 were found to be most active in inhibiting breast cancer cells (MCF-7) proliferation with IC50 values of 6.7 and 3.6 microM, respectively. The activity of AC2 is almost doubled and of AC5 almost tripled as compared to curcumin. Their selectivity towards different cell lines is also more noticeable. Compounds AC2 and AC5 also showed increased activity against a human prostate cancer cell line (DU-145) and non-small lung cancer cell line (NCI-H460) with IC50 values of 20.4, 16.3 and 18.3, 10.7 microM, respectively.