Design, Synthesis, Cytoselective Toxicity, Structure–Activity Relationships, and Pharmacophore of Thiazolidinone Derivatives Targeting Drug-Resistant Lung Cancer Cells

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 13, 2008
• 年：2008
• 卷：51
• 期：5
• 页码：1242 - 1251
• 全文大小：1872K
• 年卷期：v.51,no.5(March 13, 2008)
• ISSN：1520-4804

文摘

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 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 H460_taxR and modeling using a previously validated P-gp substrate pharmacophore suggested that active compounds were not likely P-gp substrates.