Structure-based design: Synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors
Structure-based design: Synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors
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DOI：
10.1021/jm050019i
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发表时间：
2005-05-19
影响因子：
7.3
通讯作者：
Mitsuya, H
中科院分区：
文献类型：
--
作者：
Ghosh, AK;Swanson, LM;Mitsuya, H
基于结构设计合成了一系列新型非肽类HIV蛋白酶抑制剂。根据抑制剂I（UIC-94017）结合的HIV-1蛋白酶的X射线晶体结构设计抑制剂。抑制剂将3-羟基水杨酸衍生的无环和环状P2配体掺入（R）-（羟乙基氨基）磺酰胺等排体中。该抑制剂仅含有两个手性中心，并且容易以光学活性形式合成，利用Sharpless不对称环氧化、区域选择性环氧化物开环和闭环烯烃复分解，使用Grubbs催化剂作为关键步骤。我们合成了13-15元环酰胺类化合物，并在MT-2细胞中评价了它们对HIV-1蛋白酶的抑制和抗病毒活性。有趣的是，所有环酰胺衍生的抑制剂明显比相应的无环化合物更有效。环的大小和取代基的影响进行了研究。结果表明，HIV-1蛋白酶的S-1-S-2活性位点优先选择14元饱和环。大环化合物26显示出优异的酶抑制效力，Ki值为0.7 nM，抗病毒IC 50值为0.3 μ M。鉴于其结构简单和初步的有趣的结果，这些抑制剂的进一步优化正在进行中。
The structure-based design and synthesis of a series of novel nonpeptide HIV protease inhibitors are described. The inhibitors were designed based upon the X-ray crystal structure of inhibitor I (UIC-94017)-bound HIV-1 protease. The inhibitors incorporated 3-hydroxysalicyclic acid-derived acyclic and cyclic P2 ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. The inhibitors contain only two chiral centers and are readily synthesized in optically active form utilizing Sharpless asymmetric epoxidation, regioselective epoxide opening, and ring-closing olefin metathesis using Grubbs' catalyst as the key steps. We have synthesized 13-15-membered cycloamides and evaluated their HIV-1 protease enzyme inhibitory and antiviral activities in MT-2 cells. Interestingly, all cycloamide-derived inhibitors are noticeably more potent than the corresponding acyclic compounds. The ring size and substituent effects were investigated. It turned out that the 14-membered saturated ring is preferred by the S-1-S-2 active sites of HIV-1 protease. Macrocycle 26 showed excellent enzyme inhibitory potency with a K-i value of 0.7 nM and an antiviral IC50 value of 0.3 mu M. In view of their structural simplicity and preliminary interesting results, further optimization of these inhibitors is underway.