Synthesis and Structure鈥揂ctivity Evaluation of Isatin-尾-thiosemicarbazones with Improved Selective Activity toward Multidrug-Resistant Cells Expressing P-Glycoprotein

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• 作者：Matthew D. Hall ; Kyle R. Brimacombe ; Matthew S. Varonka ; Kristen M. Pluchino ; Julie K. Monda ; Jiayang Li ; Martin J. Walsh ; Matthew B. Boxer ; Timothy H. Warren ; Henry M. Fales ; Michael M. Gottesman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5878-5889
• 全文大小：992K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

Cancer multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters presents a significant unresolved clinical challenge. One strategy to resolve MDR is to develop compounds that selectively kill cells overexpressing the efflux transporter P-glycoprotein (MDR1, P-gp, ABCB1). We have previously reported structure鈥揳ctivity studies based around the lead compound NSC73306 (1, 1-isatin-4-(4鈥?methoxyphenyl)-3-thiosemicarbazone, 4.3-fold selective). Here we sought to extend this work on MDR1-selective analogues by establishing whether 1 showed 鈥渞obust鈥?activity against a range of cell lines expressing P-gp. We further aimed to synthesize and test analogues with varied substitution at the N4-position, and substitution around the N4-phenyl ring of isatin-尾-thiosemicarbazones (IBTs), to identify compounds with increased MDR1-selectivity. Compound 1 demonstrated MDR1-selectivity against all P-gp-expressing cell lines examined. This selectivity was reversed by inhibitors of P-gp ATPase activity. Structural variation at the 4鈥?phenyl position of 1 yielded compounds of greater MDR1-selectivity. Two of these analogues, 1-isatin-4-(4鈥?nitrophenyl)-3-thiosemicarbazone (22, 8.3-fold selective) and 1-isatin-4-(4鈥?tert-butyl phenyl)-3-thiosemicarbazone (32, 14.8-fold selective), were selected for further testing and were found to retain the activity profile of 1. These compounds are the most active IBTs identified to date.