Yuka Nakanishi

Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells

Extracts from the seeds of milk thistle, Silybum marianum, are known commonly as silibinin and silymarin and possess anticancer actions on human prostate carcinoma in vitro and in vivo. Seven distinct flavonolignan compounds and a flavonoid have been isolated from commercial silymarin extracts. Most notably, two pairs of diastereomers, silybin A and silybin B and isosilybin A and isosilybin B, are among these compounds. In contrast, silibinin is composed only of a 1:1 mixture of silybin A and silybin B. With these isomers now isolated in quantities sufficient for biological studies, each pure compound was assessed for antiproliferative activities against LNCaP, DU145, and PC3 human prostate carcinoma cell lines. Isosilybin B was the most consistently potent suppressor of cell growth relative to either the other pure constituents or the commercial extracts. Isosilybin A and isosilybin B were also the most effective suppressors of prostate-specific antigen secretion by androgen-dependent LNCaP cells. Silymarin and silibinin were shown for the first time to suppress the activity of the DNA topoisomerase IIalpha gene promoter in DU145 cells and, among the pure compounds, isosilybin B was again the most effective. These findings are significant in that isosilybin B composes no more than 5% of silymarin and is absent from silibinin. Whereas several other more abundant flavonolignans do ultimately influence the same end points at higher exposure concentrations, these findings are suggestive that extracts enriched for isosilybin B, or isosilybin B alone, might possess improved potency in prostate cancer prevention and treatment.

Antitumor agents. Part 214: synthesis and evaluation of curcumin analogues as cytotoxic agents.

Fifty-eight curcumin analogues were prepared and evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. Compound was the most potent analogue against several cell lines, including HOS (bone cancer) and 1A9 (breast cancer), with ED50 values of 0.97 and <0.63 microg/mL, respectively.

A Novel Bridged Stilbenoid Trimer and Four Highly Condensed Stilbenoid Oligomers in Vatica rassak.

Abstract Vaticanol G ( 1 ) and vaticaside D ( 2 ) isolated from stem bark of Vatica rassak (Dipterocarpaceae) were the first instance of stilbenoid trimers with an unusual tribenzobicyclo[3.3.2]decatriene system. Vaticanols D ( 3 ) and H ( 4 )–J ( 6 ) were elucidated to be a stilbenoid hexamer or heptamer containing a structurally identical trimeric unit. Their structures and the relative configurations were established on the basis of 2D NMR spectroscopy. The hexamers ( 3 , 4 and 5 ) and the heptemer ( 6 ) showed cytotoxicity against KB cells.

Bioactive constituents of the stem bark of Mitrephora glabra

Bioactivity-guided fractionation of the stem bark of Mitrephora glabra yielded nine compounds, comprising three ent-kaurenoids (1-3), five polyacetylenic acids/esters (4-8), and one aporphine alkaloid, liriodenine (9). The structures of the six new compounds (1-3, 5, 7, and 8) were determined by spectroscopic data interpretation. All compounds were evaluated for their inhibitory activities against a panel of cancer cell lines and a battery of microorganisms.

A new resveratrol octamer, vateriaphenol A, in Vateria indica

Abstract A novel resveratrol octamer, vateriaphenol A, was isolated from stem bark of Vateria indica (Dipterocarpaceae). The structure and the relative configuration were confirmed on the basis of 1D and 2D NMR spectral data. Vateriaphenol A showed cytotoxicity against KB cells.

Pyrrolizidine alkaloids from Echium glomeratum (Boraginaceae).

The methanolic extract of the whole plant of Echium glomeratum Poir. (Boraginaceae) has afforded five pyrrolizidine alkaloids, three that were (7S, 8R)-petranine (1), (7S, 8S)-petranine (2), and (7R, 8R)-petranine (3a) or (7R, 8S)-petranine (3b), comprising a tricyclic pyrrolizidine alkaloids subclass; and two that were known but to the species: 7-angeloylretronecine (4) and 9-angeloylretronecine (5). All compounds were tested against a human tumor panel for cytotoxicity; no activity was observed (EC50 values>20microg/ml).

Antitumor agents. Part 212: Bucidarasins A–C, three new cytotoxic clerodane diterpenes from Bucida buceras

As part of a study on antitumor agents from rainforest plants, four new clerodane diterpenes, bucidarasins A--D (1-4), were isolated from Bucida buceras. Their structures were elucidated from detailed 2D NMR analyses. Compounds 1-3 showed potent cytotoxicity against human tumor cell lines with IC(50) values of 0.5-1.9 microM. The potency was retained in drug resistant lines.

Phytochemical studies and cytotoxicity evaluations of Colchicum tunicatum Feinbr and Colchicum hierosolymitanum Feinbr (Colchicaceae): Two native Jordanian meadow saffrons.

As a part of our continuing investigation of Jordanian Colchicum species, the biologically active components of Colchicum hierosolymitanum Feinbr and Colchicum tunicatum Feinbr (Colchicaceae) were pursued. The brine shrimp lethality test (BSLT) was used to direct the fractionation and isolation of active components. Five and four known colchicinoids were isolated and characterized from C. tunicatum and C. hierosolymitanum, respectively. The known colchicinoids, reported for the first time from these two species are: (−)-colchicine (I), 3-demethyl-(−)-colchicine (II), (−)-cornigerine (III), β-lumicolchicine (IV), and (−)-androbiphenyline (V) from C. tunicatum, and (−)-colchicine (I), 2-demethyl-(−)-colchicine (VI), (−)-cornigerine (III), and β-lumicolchicine (IV) from C. hierosolymitanum. The chemical structures of the isolated compounds have been elucidated using a series of spectroscopic and spectrometric techniques principally; 1D-NMR (1H and 13C) and low resolution EI-MS and APCIMS. All pure compounds were evaluated for cytotoxicity against three human cancer cell lines; MCF-7 human breast carcinoma, NCI-H460 human large cell lung carcinoma, and SF-268 human astrocytoma. (−)-Colchicine (I) and (−)-cornigerine (III) were found to be the most bioactive of the identified compounds with EC50 values in the range of 0.016–0.097 μM.

Antitumor agents. Part 218: Cappamensin A, a new In vitro anticancer principle, from Capparis sikkimensis.

A new inhibitor of in vitro tumor cell replication, cappamensin A (1) (2H-1,4-benzoxazin-3(4H)-one, 6-methoxy-2-methyl-4-carbaldehyde), was isolated from the roots of Capparis sikkimensis subsp. formosana using bioactivity-guided fractionation. The structure of 1 was established by spectroscopic methods, including 2D NMR analyses. Compound 1 displayed significant in vitro anticancer activity against ovarian (1A9), lung (A549), ileocecal (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine resistant (KB-VIN) human tumor cell lines with ED(50) values </=4 microgram/mL (mean GI(50) value of 15.1 microM).

Large-Scale Isolation of Flavonolignans from Silybum marianum Extract Affords New Minor Constituents and Preliminary Structure-Activity Relationships

The gram-scale isolation of the major flavonolignan diastereoisomers from milk thistle ( Silybum marianum) extract provided an entree into the isolation of two related analogues that are present in extremely minute quantities. The isolation and structure elucidation of these two new compounds, which we have termed isosilybin C and isosilybin D due to their structural similarities to isosilybin A and isosilybin B, respectively, afforded a preliminary analysis of structure-activity relationships toward prostate cancer growth, survival, and apoptotic endpoints.