Design, synthesis, cytoselective toxicity, structure-activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells

Hongyu Zhou, Shuhong Wu, Shumei Zhai, Aifeng Liu, Ying Sun, Rongshi Li, Ying Zhang, Sean Ekins, Peter W. Swaan, Bingliang Fang, Bin Zhang, Bing Yan

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153 Scopus citations


Ten cytoselective compounds have been identified from 372 thiazolidinone analogues by applying iterative library approaches. These compounds selectively killed both non-small cell lung cancer cell line H460 and its paclitaxel-resistant variant H460taxR at an IC50 between 0.21 and 2.93 μM while showing much less toxicity to normal human fibroblasts at concentrations up to 195 μM. Structure-activity relationship studies revealed that (1) the nitrogen atom on the 4-thiazolidinone ring (ring B in Figure 1) cannot be substituted, (2) several substitutions on ring A are tolerated at various positions, and (3) the substitution on ring C is restricted to the -NMe2 group at the 4-position. A pharmacophore derived from active molecules suggested that two hydrogen bond acceptors and three hydrophobic regions were common features. Activities against P-gp-overexpressing and paclitaxel-resistant cell line H460taxR and modeling using a previously validated P-gp substrate pharmacophore suggested that active compounds were not likely P-gp substrates.

Original languageEnglish (US)
Pages (from-to)1242-1251
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number5
Publication statusPublished - Mar 13 2008


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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