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J Med Chem. 2008 Mar 13;51(5):1242-51. doi: 10.1021/jm7012024. Epub 2008 Feb 8.

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

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Department of Chemical Biology and Therapeutics, St. Jude Research Hospital, Memphis, Tennessee 38105, USA.


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 H460 taxR at an IC 50 between 0.21 and 2.93 microM while showing much less toxicity to normal human fibroblasts at concentrations up to 195 microM. 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 -NMe 2 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 H460 taxR and modeling using a previously validated P-gp substrate pharmacophore suggested that active compounds were not likely P-gp substrates.

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