阿糖腺苷和缬氨酸-丝氨酸前药的合成、转运及抗病毒活性。
Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir.
机构信息
Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744, USA.
出版信息
Bioorg Med Chem Lett. 2011 Jul 1;21(13):4045-9. doi: 10.1016/j.bmcl.2011.04.126. Epub 2011 May 3.
Abstract
We report the synthesis and biological evaluation of Ala-(Val-)l-Ser-CO(2)R prodrugs of 1, where a dipeptide promoiety is conjugated to the P(OH)(2) group of cidofovir (1) via esterification by the Ser side chain hydroxyl group and an ethyl group (4 and 5) or alone (6 and 7). In a murine model, oral administration of 4 or 5 did not significantly increase total cidofovir species in the plasma compared to 1 or 2, but 7 resulted in a 15-fold increase in a rat model and had an in vitro EC(50) value against human cytomegalovirus comparable to 1. Neither 6 nor 7 exhibited toxicity up to 100 μM in KB or HFF cells.
摘要
我们报告了 Ala-（Val-）l-Ser-CO(2)R 前药的合成和生物学评价，其中通过 Ser 侧链羟基和乙基（4 和 5）或单独（6 和 7）将二肽促进物与cidofovir（1）的 P(OH)(2)基团酯化。在小鼠模型中，与 1 或 2 相比，口服给予 4 或 5 并没有显著增加血浆中总cidofovir 种类，但 7 在大鼠模型中增加了 15 倍，并且对人巨细胞病毒的体外 EC(50)值与 1 相当。在 KB 或 HFF 细胞中，6 和 7 均未表现出毒性，最高可达 100 μM。
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