Design and Synthesis of Human ABCB1 (P-Glycoprotein) Inhibitors by Peptide Coupling of Diverse Chemical Scaffolds on Carboxyl and Amino Termini of (S)-Valine-Derived Thiazole Amino Acid

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• 作者：Satyakam Singh ; Nagarajan Rajendra Prasad ; Eduardo E. Chufan ; Bhargav A. Patel ; Yi-Jun Wang ; Zhe-Sheng Chen ; Suresh V. Ambudkar ; Tanaji T. Talele
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4058-4072
• 全文大小：759K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

P-glycoprotein (P-gp) serves as a therapeutic target for the development of multidrug resistance reversal agents. In this study, we synthesized 21 novel compounds by peptide coupling at corresponding carboxyl and amino termini of (S)-valine-based bis-thiazole and monothiazole derivatives with diverse chemical scaffolds. Using calcein-AM efflux assay, we identified compound 28 (IC₅₀ = 1.0 渭M) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitter-ion. Compound 28 inhibited the photolabeling of P-gp with [¹²⁵I]-iodoarylazidoprazosin with IC₅₀ = 0.75 渭M and stimulated the basal ATP hydrolysis of P-gp in a concentration-dependent manner (EC₅₀ ATPase = 0.027 渭M). Compound 28 at 3 渭M reduced resistance in cytotoxicity assay to paclitaxel in P-gp-expressing SW620/Ad300 and HEK/ABCB1 cell lines. Biochemical and docking studies showed site-1 to be the preferable binding site for 28 within the drug-binding pocket of human P-gp.