Griffith Institute for Drug Discovery , Griffith University , Brisbane , QLD 4111 , Australia.
Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation , Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute , Brisbane , QLD 4102 , Australia.
J Nat Prod. 2018 Apr 27;81(4):838-845. doi: 10.1021/acs.jnatprod.7b00929. Epub 2018 Feb 23.
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.
天然存在的五环二萜赤霉素（1）被用于使用平行溶液相合成生成类药性酰胺文库。在合成之前，根据类药性物理化学参数（如 log P、氢键供体/受体数和分子量）生成并优先考虑虚拟文库。通过分析 NMR、MS、UV 和 IR 数据阐明了合成类似物（2-13）的结构。化合物 12 提供了结晶材料，其结构通过 X 射线晶体学分析得到证实。所有化合物均在体外进行了细胞毒性和 LNCaP 前列腺癌细胞中脂质代谢失调的评估。虽然在所测试的浓度下未鉴定出细胞毒性活性，但合成的类似物 3、5、7、10 和 11 显著降低了前列腺癌细胞中游离胆固醇的细胞摄取，表明赤霉素衍生物在调节胆固醇代谢方面具有新的作用。
