Liu Chao, Dumbre Shrinivas G, Pannecouque Christophe, Korba Brent, De Jonghe Steven, Herdewijn Piet
KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium.
Org Biomol Chem. 2017 Jul 5;15(26):5513-5528. doi: 10.1039/c7ob01265a.
l-α-2'-Deoxythreosyl nucleoside phosphonates and their phosphonodiamidate prodrugs with a hypoxanthine, 2,6-diaminopurine, 2-amino-6-cyclopropylaminopurine, 7-deazaadenine, 5-fluorouracil and 5-methylcytosine heterocycle as a nucleobase were synthesized and evaluated for their inhibitory activity against HIV and HBV. The 2,6-diaminopurine modified analogue 23a displayed the most potent activity against HIV, with an EC value of 11.17 μM against HIV-1 (III) and an EC value of 8.15 μM against HIV-2 (ROD). The application of the prodrug strategy on nucleoside phosphonate 23a led to a 200-fold boost in anti-HIV potency. None of the compounds showed any activity against HBV at the highest concentration tested.
合成了以次黄嘌呤、2,6-二氨基嘌呤、2-氨基-6-环丙基氨基嘌呤、7-脱氮腺嘌呤、5-氟尿嘧啶和5-甲基胞嘧啶杂环作为碱基的l-α-2'-脱氧苏糖核苷膦酸酯及其膦酰二氨基酯前药，并评估了它们对HIV和HBV的抑制活性。2,6-二氨基嘌呤修饰的类似物23a对HIV表现出最有效的活性，对HIV-1（III）的EC值为11.17 μM，对HIV-2（ROD）的EC值为8.15 μM。在前药策略应用于核苷膦酸酯23a后，抗HIV效力提高了200倍。在测试的最高浓度下，没有一种化合物对HBV表现出任何活性。
