Minor Withanolides of Physalis longifolia: Structure and Cytotoxicity

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概要

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• 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 Δ2-1-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 IC50 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.

著者

• Cohen Mark

  Department Of Pathology University Hospitals Of Cleveland And Case Western Reserve University

• Timmermann Barbara

  Department Of Pharmacology And Toxicology College Of Pharmacy The University Of Arizona

• Gollapudi Rao

  Department of Medicinal Chemistry, School of Pharmacy, University of Kansas

• Kindscher Kelly

  Kansas Biological Survey, University of Kansas

• Day Victor

  The Small-Molecule X-ray Crystallography Laboratory, University of Kansas

• Cohen Mark

  Department of Surgery, School of Medicine, University of Kansas

• Aubé Jeffrey

  Department of Medicinal Chemistry, School of Pharmacy, University of Kansas

• Motiwala Hashim

  Department of Medicinal Chemistry, School of Pharmacy, University of Kansas

• Zhang Huaping

  Department of Medicinal Chemistry, School of Pharmacy, University of Kansas

• Samadi Abbas

  Department of Surgery, School of Medicine, University of Kansas

• Aubé Jeffrey

  Department of Medicinal Chemistry, School of Pharmacy, University of Kansas

• Timmermann Barbara

  Department of Medicinal Chemistry, School of Pharmacy, University of Kansas

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• Minor Withanolides of Physalis longifolia: Structure and Cytotoxicity

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