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

The naturally occurring pentacyclic diterpenoid gibberellic acid (<b>1</b>) 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 (<b>2</b>–<b>13</b>) were elucidated following analysis of the NMR, MS, UV, and IR data. Compound <b>12</b> afforded crystalline material, and its structure was confirmed by X-ray crystallographic analysis. All compounds were evaluated <i>in vitro</i> for cytotoxicity and deregulation of lipid metabolism in LNCaP prostate cancer cells. While no cytotoxic activity was identified at the concentrations tested, synthesized analogues <b>3</b>, <b>5</b>, <b>7</b>, <b>10</b>, and <b>11</b> substantially reduced cellular uptake of free cholesterol in prostate cancer cells, suggesting a novel role of gibberellic acid derivatives in deregulating cholesterol metabolism