title: Minor withanolides of Physalis longifolia: structure and cytotoxicity.
abstract: In our recent publication on bioactive guided isolation of compounds from Physalis longifolia (Solanaceae) novel anti-proliferative agents withalongolides A (4) and B (5), and their highly cytotoxic analogues, withalongolide A 4,19,27-triacetate (4a) and withalongolide B 4,19-diacetate (5a) were elucidated. In this study, the two lead compounds (4, 5) were re-isolated in gram quantities for the purpose of further analogue preparation and in vivo testing that would continue to probe structure-activity relationships. During this process, two additional withanolides, named withalongolides O (1) and P (2), were elucidated. Their structures were determined by spectroscopic techniques with 1 being subsequently confirmed by X-ray crystallographic analysis. Utilizing a MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] viability assay, withalongolide O (1) and its 4,7-diaceatate (1a), both containing the functionalities of Δ(2)-1-oxo- in A ring, a 5β,6β-epoxy in B ring, and a lactone ring in the nine-carbon side chain, exhibited potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal lung fibroblast (MRC-5) cells with IC(50) values in the range between 0.15 and 2.95 µM. In addition, the previously reported α orientation of 7-acetate group in acnistins C and D should be revised to the β orientation on the basis of NMR data comparison.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Huaping
authors.initials: H
authors.lastname: Zhang
authors.forename: Hashim
authors.initials: H
authors.lastname: Motiwala
authors.forename: Abbas
authors.initials: A
authors.lastname: Samadi
authors.forename: Victor
authors.initials: V
authors.lastname: Day
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.forename: Mark
authors.initials: M
authors.lastname: Cohen
authors.forename: Kelly
authors.initials: K
authors.lastname: Kindscher
authors.forename: Rao
authors.initials: R
authors.lastname: Gollapudi
authors.forename: Barbara
authors.initials: B
authors.lastname: Timmermann
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D008545:Melanoma / Q000188:drug therapy; D008958:Models, Molecular; D032321:Physalis / Q000737:chemistry*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013329:Structure-Activity Relationship; D054358:Withanolides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D054358:Withanolides