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

Journal of Natural Products
Folake A EgbewandeRohan A Davis

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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Citations

Mar 3, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mario WibowoRohan A Davis
Nov 7, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Folake A EgbewandeRohan A Davis
May 23, 2018·The Journal of Organic Chemistry·David J-Y D BonPing Lan

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