Identification of Gibberellic Acid Derivatives That Deregulate Cholesterol Metabolism in Prostate Cancer Cells

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Egbewande, Folake A
Sadowski, Martin C
Levrier, Claire
Tousignant, Kaylyn D
White, Jonathan M
Coster, Mark J
Nelson, Colleen C
Davis, Rohan A
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2018
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Abstract

The naturally occurring pentacyclic diterpenoid gibberellic acid (1) was used in the generation of a drug-like amide library using parallel-solution-phase synthesis. Prior to the synthesis, a virtual library was generated and prioritized based on drug-like physicochemical parameters such as log P, hydrogen bond donor/acceptor counts, and molecular weight. The structures of the synthesized analogues (2–13) were elucidated following analysis of the NMR, MS, UV, and IR data. Compound 12 afforded crystalline material, and its structure was confirmed by X-ray crystallographic analysis. All compounds were evaluated in vitro for cytotoxicity and deregulation of lipid metabolism in LNCaP prostate cancer cells. While no cytotoxic activity was identified at the concentrations tested, synthesized analogues 3, 5, 7, 10, and 11 substantially reduced cellular uptake of free cholesterol in prostate cancer cells, suggesting a novel role of gibberellic acid derivatives in deregulating cholesterol metabolism.

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Journal of Natural Products

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81

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4

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This document is the Postprint of a Published Work that appeared in final form in Journal of Natural Products, copyright 2018 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see 10.1021/acs.jnatprod.7b00929

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Chemical sciences

Biological sciences

Biomedical and clinical sciences

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