†Eskitis 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. 2015 Apr 24;78(4):914-8. doi: 10.1021/np500856u. Epub 2015 Mar 24.
The fungal metabolite 3-chloro-4-hydroxyphenylacetic acid (1) was utilized in the generation of a unique drug-like screening library using parallel solution-phase synthesis. A 20-membered amide library (3-22) was generated by first converting 1 to methyl (3-chloro-4-hydroxyphenyl)acetate (2), then reacting this scaffold with a diverse series of primary amines via a solvent-free aminolysis procedure. The structures of the synthetic analogues (3-22) were elucidated by spectroscopic data analysis. The structures of compounds 8, 12, and 22 were confirmed by single X-ray crystallographic analysis. All compounds were evaluated for cytotoxicity against a human prostate cancer cell line (LNCaP) and for antiparasitic activity toward Trypanosoma brucei brucei and Plasmodium falciparum and showed no significant activity at 10 μM. The library was also tested for effects on the lipid content of LNCaP and PC-3 prostate cancer cells, and it was demonstrated that the fluorobenzyl analogues (12-14) significantly reduced cellular phospholipid and neutral lipid levels.
真菌代谢产物 3-氯-4-羟基苯乙酸（1）被用于使用平行溶液相合成来生成独特的类药性筛选文库。通过首先将 1 转化为甲酯（3-氯-4-羟基苯）乙酸（2），然后通过无溶剂的氨解程序使该支架与各种系列的伯胺反应，生成了一个 20 成员酰胺文库（3-22）。通过光谱数据分析阐明了合成类似物（3-22）的结构。通过单晶 X 射线晶体学分析确认了化合物 8、12 和 22 的结构。所有化合物均在 10 μM 时对人前列腺癌细胞系（LNCaP）的细胞毒性和对 Trypanosoma brucei brucei 和 Plasmodium falciparum 的抗寄生虫活性进行了评估，均无明显活性。该文库还测试了对 LNCaP 和 PC-3 前列腺癌细胞中脂质含量的影响，结果表明氟苄基类似物（12-14）显著降低了细胞磷脂和中性脂质水平。
