Design, synthesis, cytoselective toxicity, structure-activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells.
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| Abstract |
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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| Authors | 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 |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 5 Pg. 1242-51 (Mar 13 2008) ISSN: 0022-2623 [Print] United States |
| PMID | 18257542 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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