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

Yin Liu, Fei Li, Ling Wu, Wenyi Wang, Hao Zhu, Qiu Zhang, Hongyu Zhou, Bing Yan

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 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 R1, R2 and R3 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.

Original languageEnglish (US)
Pages (from-to)1971-1975
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number9
DOIs
StatePublished - May 1 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Keywords

  • Aqueous solubility
  • Cytotoxicity
  • Lead optimization
  • NSCLC
  • Thiazolidinone

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