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

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-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 μg/ml) and anti-cancer activity (10-fold improvement in EC50 from 0.72-0.98 μM to 0.08-0.16 μM) in the new lead thiazolidinone compound 31.