Novel C²-purine position analogs of nitrobenzylmercaptopurine riboside as human equilibrative nucleoside transporter 1 inhibitors

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• 作者：Amol Gupte ; John K. Buolamwini
• 关键词：Nucleoside transporter inhibitors ; Nitrobenzylmercaptopurine riboside (NBMPR) ; Analogs ; Flow cytometry ; Binding affinity ; Synthesis ; Structure– ; activity relationship (SAR) ; Equilibrative nucleoside transporter 1
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2007
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 December 2007
• 卷：15
• 期：24
• 页码：7726-7737
• 文件大小：247 K

摘要

Nucleoside transporter inhibitors have potential therapeutic applications as anticancer, antiviral, cardioprotective, and neuroprotective agents. S⁶-(4-nitrobenzyl)mercaptopurine riboside (NBMPR) is a prototype inhibitor of the human equilibrative nucleoside transporter (hENT1), and is a high affinity ligand with a K_d of 0.1–1.0 nM. We have synthesized and flow cytometrically evaluated the binding affinity of a series of novel C²-purine position substituted analogs of NBMPR at the hENT1. The aim of this research was to understand the substituent requirements at the C²-purine position of NBMPR. Structure–activity relationships (SAR) indicate that increasing the steric bulk at the C²-purine position of NBMPR led to a decrease in binding affinity of these ligands at the hENT1. New high affinity inhibitors were identified, with the best compound, 2-fluoro-4-nitrobenzyl mercaptopurine riboside (7), exhibiting a K_i of 2.1 nM. This information, when coupled with the information obtained from other structure–activity relationship studies should prove useful in efforts aimed at modeling the NMBPR and analogs pharmacophore of hENT1 inhibitors.