新型2',3'-二脱氧-4'-硒代核苷作为潜在抗病毒药物的设计与合成

Design and synthesis of novel 2',3'-dideoxy-4'-selenonucleosides as potential antiviral agents.

作者信息

Jeong Lak Shin, Choi Yoo Na, Tosh Dilip K, Choi Won Jun, Kim Hea Ok, Choi Jungwon

机构信息

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.

出版信息

Bioorg Med Chem. 2008 Dec 1;16(23):9891-7. doi: 10.1016/j.bmc.2008.10.034. Epub 2008 Oct 17.

DOI:10.1016/j.bmc.2008.10.034

PMID:18977147

Abstract

On the basis of potent anti-HIV activity of 2',3'-dideoxynucleosides (ddNs), their bioisosteric analogues, 2',3'-dideoxy-4'-selenonucleosides (4'-seleno-ddNs) were first synthesized from a chiral template, d-glutamic acid using stereoselective ring-closure reaction of the dimesylate with Se(2-) and Pummerer type condensation of the selenoxide with nucleobases as key steps. X-ray crystallographic analysis indicated that 4'-seleno-ddNs adopted the same C2'-endo/C3'-exo (South) conformation as anti-HIV active ddNs, but did not show anti-HIV activity, indicating that RT seems to prefer the C2'-exo/C3'-endo (North) conformation on binding with their triphosphates.

摘要

基于2'，3'-二脱氧核苷（ddNs）具有强大的抗HIV活性，其生物电子等排类似物2'，3'-二脱氧-4'-硒代核苷（4'-硒代-ddNs）首先通过手性模板d-谷氨酸合成，以二甲磺酸酯与Se(2-)的立体选择性闭环反应以及亚硒氧化物与核苷碱基的普默勒尔型缩合反应为关键步骤。X射线晶体学分析表明，4'-硒代-ddNs采用了与抗HIV活性ddNs相同的C2'-内型/C3'-外型（南方）构象，但未显示出抗HIV活性，这表明逆转录酶（RT）在与它们的三磷酸酯结合时似乎更喜欢C2'-外型/C3'-内型（北方）构象。