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Improving both aqueous solubility and anti-cancer activity by assessing progressive lead optimization libraries.

ABSTRACT: Thiazolidinone compounds 1-3 are lead compounds that have cytoselective toxicity toward non-small cell lung cancer (NSCLC) cells and drug-resistant NSCLC cells while showing low toxicity to normal human fibroblasts (NHFB). However, this class of compounds generally has a very low aqueous solubility (?0.1 ?g/ml). In order to improve both solubility and anti-cancer activity, we designed and synthesized two lead-optimization libraries and investigated these libraries using simultaneous high-throughput solubility and cytotoxicity assays. By all-around modifications on R(1), R(2) and R(3) substitutions, consecutive library synthesis, and testing, we improved the aqueous solubility (5-fold improvement in solubility, from 0.1 to 0.5 ?g/ml) and anti-cancer activity (10-fold improvement in EC50 from 0.72-0.98 ?M to 0.08-0.16 ?M) in the new lead thiazolidinone compound 31.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5586103 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Improving both aqueous solubility and anti-cancer activity by assessing progressive lead optimization libraries.

Liu Yin Y Li Fei F Wu Ling L Wang Wenyi W Zhu Hao H Zhang Qiu Q Zhou Hongyu H Yan Bing B

Bioorganic & medicinal chemistry letters 20150314 9

Thiazolidinone compounds 1-3 are lead compounds that have cytoselective toxicity toward non-small cell lung cancer (NSCLC) cells and drug-resistant NSCLC cells while showing low toxicity to normal human fibroblasts (NHFB). However, this class of compounds generally has a very low aqueous solubility (∼0.1 μg/ml). In order to improve both solubility and anti-cancer activity, we designed and synthesized two lead-optimization libraries and investigated these libraries using simultaneous high-through ...[more]

PMID: 25827524

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