Yumiko Kimura

Triterpene acids from the leaves of Perilla frutescens and their anti-inflammatory and antitumor-promoting effects

Nine triterpene acids, viz., six of the ursane type, ursolic acid (1), corosolic acid (2), 3-epicorosolic acid (3), pomolic acid (4), tormentic acid (5) and hyptadienic acid (6), and three of the oleanane type, oleanolic acid (7), augustic acid (8) and 3-epimaslinic acid (9), among which 1 constituted the most predominant triterpene acid, were isolated and identified from ethanol extracts of the leaves of red perilla [Perilla frutescens (L.) Britton var. acuta Kudo] and green perilla [P. frutescens (L.) Britton var. acuta Kudo forma viridis Makino]. These eight compounds, 1, 2, 4–9, were evaluated for their inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 μg/ear) in mice. All the compounds tested showed a marked anti-inflammatory effect, with a 50% inhibitory dose (ID50) of 0.09–0.3 mg per ear. In addition, an evaluation against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA showed five compounds, 1–3, 5 and 9, with a potent inhibitory effect on EBV-EA induction (91–93% inhibition at 1×103 mol ratio/TPA). Furthermore, compound 5 exhibited strong antitumor-promoting activity in an in vivo two-stage carcinogenesis test of mouse tumor by using 7,12-dimethylbenz(a)anthracene (DMBA) as an initiator and TPA as a promoter.

Cytotoxic and apoptosis-inducing activities of triterpene acids from Poria cocos.

Six lanostane-type triterpene acids (1a-6a), isolated from Poria cocos , and their methyl ester (1b-6b) and hydroxy derivatives (1c-6c) were prepared. Upon evaluation of the cytotoxic activity of these compounds against leukemia (HL60), lung (A549), melanoma (CRL1579), ovary (NIH:OVCAR-3), breast (SK-BR-3), prostate (DU145), stomach (AZ521), and pancreas (PANC-1) cancer cell lines, 11 compounds (5a, 6a, 2b-5b, 1c, and 3c-6c) exhibited activity with single-digit micromolar IC(50) values against one or more cell lines. Poricotriol A (1c), a hydroxy derivative of poricoic acid A (1a), exhibited potent cytotoxicities against six cell lines with IC(50) values of 1.2-5.5 μM. Poricotriol A induced typical apoptotic cell death in HL60 and A549 cells on evaluation of the apoptosis-inducing activity by flow cytometric analysis. Western blot analysis in HL60 cells showed that poricotriol A activated caspases-3, -8, and -9, while increasing the ratio of Bax/Bcl-2. This suggested that poricotriol A induced apoptosis via both mitochondrial and death receptor pathways in HL60. On the other hand, poricotriol A did not activate caspases-3, -8, and -9, but induced translocation of apoptosis-inducing factor (AIF) from mitochondria and increased the ratio of Bax/Bcl-2 in A549. This suggested that poricotriol A induced apoptosis via the mitochondrial pathway mostly by translocation of AIF, independent from the caspase pathway in A549. Furthermore, poricotriol A was shown to possess high selective toxicity in lung cancer cells since it exhibited only weak cytotoxicity against a normal lung cell line (WI-38).

Anti-Tumor-Promoting Effects of 25-Methoxyporicoic Acid A and Other Triterpene Acids from Poria cocos

Nine new (1, 3, 5, 8, 12, 13, 15, 17, and 18) and nine known (2, 4, 6, 7, 9-11, 14, and 16) lanostane-type triterpene acids and a known diterpene acid (19) were isolated from the epidermis of the sclerotia of Poria cocos. The structures of the new compounds were established as 16alpha,27-dihydroxydehyrotrametenoic acid (1), 25-hydroxy-3-epitumulosic acid (3), 16alpha,25-dihydroxyeburiconic acid (5), 25-methoxyporicoic acid A (8), 26-hydroxyporicoic acid DM (12), 25-hydroxyporicoic acid C (13), poricoic acid GM (15), poricoic acid HM (17), and 6,7-dehydroporicoic acid H (18), on the basis of spectroscopic methods. On evaluation of the nine new and two of the known compounds, 4 and 19, against the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, all of the compounds exhibited inhibitory effects, with IC(50) values in the range 187-348 mol ratio/32 pmol TPA. In addition, compound 8 exhibited an inhibitory effect on skin tumor promotion in an in vivo two-stage carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. Further, 17 compounds, 1-14, 16, 18, and 19, were evaluated for their cytotoxic activity against two human tumor cell lines, HL60 (leukemia) and CRL1579 (melanoma).

Cycloartane triterpenes from the fruit peel of Musa sapientum

Five novel cycloartane-type triterpenes were isolated from the nonsaponifiable lipids obtained from the methanol extract of the fruit peel of Musa sapientum L. (banana). Their structures were determined to be 3-epicycloeucalenol, 3-epicyclomusalenol, 24-methylenepollinastanone, 28-norcyclomusalenone and 24-oxo-29-norcycloartanone by spectroscopic and chemical methods.

7-OX0-10α-Cucurbitadienol from the seeds of Trichosanthes kirilowii and its anti-inflammatory effect

Abstract The structure of a new triterpene isolated from the seeds of Trichosanthes kirilowii was determined to be 7-oxo-10α-cucurbita-5,24-dien-3β-ol (7-oxo-10α-cucurbitadienol) by spectral and chemical methods. 7-Oxo-10α-cucurbitadienol, and its acetyl and 24-dihydro derivatives showed marked inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammation in mice. The 50% inhibitory dose of these compounds for TPA-induced inflammation (l,μgear−1)was O.4–0.7 mg ear−1.

Cytotoxic Activities and Anti-Tumor-Promoting Effects of Microbial Transformation Products of Prenylated Chalcones from Angelica keiskei

Three prenylated chalcones, 4‐hydroxyderricin (1), xanthoangelol (2), and xanthoangelol F (3), isolated from Angelica keiskei, were transformed by the fungus Aspergillus saitoi. These chalcones were converted to flavanones (i.e., 4, 8, and 12), and prenyl‐chain‐hydrated (i.e., 5, 7, 9–11, and 13) and ring‐B‐hydroxylated (i.e., 6) chalcones. The structures of three new metabolites, 7, 9, and 13, were established as 2″,3″‐dihydro‐4,3″‐dihydroxyderricin, 6″,7″‐dihydro‐7″‐hydroxyxanthoangelol, and 6″,7″‐dihydro‐7″‐hydroxyxanthoangelol F, respectively. Upon evaluation of cytotoxic activities of compounds 1–13, the metabolite 7 exhibited potent cytotoxicity against HL60 cells, and this cell death was revealed to be mostly due to apoptosis. In addition, compounds 1–4, 7–10, 12, and 13 were examined for their inhibitory effects on the induction of EpsteinBarr virus early antigen (EBV‐EA) by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in Raji cells. All compounds tested showed inhibitory effects against EBV‐EA activation with potencies higher than that of β‐carotene. Furthermore, the metabolite 13 exhibited inhibitory effect on skin tumor promotion in an in vivo two‐stage mouse skin carcinogenesis test based on 7,12‐dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter.

Dehydrotrametenonic Acid and Dehydroeburiconic Acid from Poria cocos and Their Inhibitory Effects on Eukaryotic DNA Polymerase α and β

A new lanostane-type triterpene acid, (20ξ)-3-oxolanosta-7,9(11),24-trien-21-oic acid (1; dehydrotrametenonic acid), along with a known triterpene acid, dehydroeburiconic acid (2), were isolated from the epidermis of the sclerotia of Poria cocos. The structure of 1 was analyzed on the basis of spectroscopic methods. Compounds 1 and 2 inhibited calf DNA polymerase α and rat DNA polymerase β, with the 50% inhibition values of 45.5 μM (1) and 40.8 μM (2), and 86.5 μM (1) and 30.0 μM (2), respectively.

Acyclic and incompletely cyclized triterpene alcohols in the seed oils of theaceae and gramineae.

The triterpene alcohol constituents of the non-saponifiable lipids of two Theaceae seed oils, sasanqua and camellia oils, and two Gramineae seed oils, wheat germ and rice bran oils, were investigated. This led to the isolation and characterization of one acyclic and eight incompletely cyclized triterpene alcohols. They are camelliol A, camelliol B, camelliol C, achilleol A, helianol, isohelianol, sasanquol, graminol A [(13R, 14R)-3,4-seco-25(10→9)abeo-8α,9β,10α-podioda-4,17,21-trien-3-ol], and (2Z,6Z,10Z,14E,18E)-farnesylfarnesol. Two other compounds isolated were characterized as (2Z,6Z,10E,14E)-geranylfarnesol, a sesterterpene alcohol, and phytol, a diterpene alcohol. Graminol A and (2Z,6Z,10E,14E)-geranylfarnesol are considered to be new natural products.

Sasanquol, A 3,4-seco-triterpene alcohol from sasanqua oil, and its anti-inflammatory effect

A novel 3,4-seco-triterpene alcohol, named sasanquol, was isolated from the non-saponifiable lipid of sasanqua oil from the seeds of Camellia sasanqua. Its structure was established to be 3,4-seco-D:B-friedobacchara-4,21-dien-3-ol by spectroscopic methods. This is the first example of naturally occurring triterpene with a D:B-friedobaccharane skeleton. The 50% inhibitory dose of this compound against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammation (1 microgram per ear) in mice was 0.4 mg per ear.

Antitumor-promoting effects and cytotoxic activities of dammar resin triterpenoids and their derivatives.

Nineteen known triterpenoids, 1–19, and one known sesquiterpenoid, 20, were isolated from dammar resin obtained from Shorea javanica K. & V. (Dipterocarpaceae). One of the acidic triterpenoids, dammarenolic acid (1), was converted to fourteen derivatives, namely, an alcohol, 21, an aldehyde, 22, and twelve L‐amino acid conjugates, 23–34. Compounds 1–34 were examined for their inhibitory effects on the induction of Epstein–Barr virus early antigen (EBV‐EA) by 12‐O‐tetradecanoylphorbol 13‐acetate (TPA) in Raji cells, a known primary screening test for antitumor promoters. All of the compounds tested, except for compounds 4, 5, 12–14, 16, and 17, showed inhibitory effects against EBV‐EA activation with potencies either comparable with or stronger than that of β‐carotene, a known natural antitumor promoter. In addition, (20S)‐20‐hydroxy‐3,4‐secodammara‐4(28),24‐dien‐3‐al (22) exhibited inhibitory effects on skin tumor promotion in an in vivo two‐stage mouse skin carcinogenesis test based on 7,12‐dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter. Furthermore, evaluation of the cytotoxic activities of compounds 1–34 against human cancer cell lines showed that reduction (i.e., 21 and 22) or conjugation with L‐amino acids (i.e., 23–34) of compound 1 enhanced the cytotoxicity against human melanoma cell line CRL1579.