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

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.