Modular Assembly of Purine-like Bisphosphonates as Inhibitors of HIV-1 Reverse Transcriptase

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• 作者：Cyrus M. Lacbay ; John Mancuso ; Yih-Shyan Lin ; Nicholas Bennett ; Matthias G枚tte ; Youla S. Tsantrizos
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：57
• 期：17
• 页码：7435-7449
• 全文大小：489K
• ISSN：1520-4804

文摘

Bisphosphonates can mimic the pyrophosphate leaving group of the nucleotidyl transfer reaction and effectively inhibit RNA/DNA polymerases. In a search of HIV-1 reverse transcriptase (RT) inhibitors, a new chemotype of nonhydrolyzable purine diphosphate mimic was synthesized. A modular synthetic protocol was developed, utilizing 2-amino-6-(methylthio)-4-(trimethylsilyl)nicotinonitrile as the key synthon in the preparation of highly substituted 2-aminonicotinonitriles. These building blocks were subsequently elaborated to the pyrido[2,3-d]pyrimidine bisphosphonates (PYPY-BPs). Biochemical screening identified analogs of PYPY-BPs that inhibit HIV-1 RT-catalyzed DNA synthesis.