Design of gem-difluoro-bis-tetrahydrofuran as P2 ligand for HIV-1 protease inhibitors to improve brain penetration: synthesis, X-ray studies, and biological evaluation.
Design of gem-difluoro-bis-tetrahydrofuran as P2 ligand for HIV-1 protease inhibitors to improve brain penetration: synthesis, X-ray studies, and biological evaluation.
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DOI：
10.1002/cmdc.201402358
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发表时间：
2015-01
期刊：
影响因子：
3.4
通讯作者：
Mitsuya, Hiroaki
中科院分区：
文献类型：
--
作者：
Ghosh, Arun K.;Yashchuk, Sofiya;Mizuno, Akira;Chakraborty, Nilanjana;Agniswamy, Johnson;Wang, Yuan-Fang;Aoki, Manabu;Gomez, Pedro Miguel Salcedo;Amano, Masayuki;Weber, Irene T.;Mitsuya, Hiroaki
介绍了含氟HIV-1蛋白酶抑制剂的结构设计、合成、生物学评价和X-射线结构研究。以Reformatskiii-Claisen反应为关键步骤，立体选择性地合成了偕二氟双四氢呋喃配体的两种对映体。将光学活性配体HIV-1 LAI转化为蛋白酶抑制剂。这些抑制剂中的两种（3和4）表现出在皮摩尔范围内的HIV-1蛋白酶抑制Ki。两种抑制剂均显示出非常有效的抗病毒活性，对实验室毒株HIV-1 LAI的EC 50值分别为0.8 nM和3.1 nM。与地瑞那韦相比，两种抑制剂的亲脂性均有所改善。此外，这两种抑制剂在体外模型中显示出大大改善的血脑屏障通透性。测定了抑制剂4结合的HIV-1蛋白酶的高分辨X射线结构。X-射线结构表明，氟配体与HIV-1蛋白酶S2亚位点发生了广泛的相互作用，包括与蛋白酶骨架原子的氢键相互作用。此外，双-THF配体上的两个氟原子与翼Gly 48羰基氧形成强相互作用。
Structure-based design, synthesis, biological evaluation and X-ray structural studies of fluorine containing HIV-1 protease inhibitors are described. The synthesis of both enantiomers of the gem-difluoro-bis-THF ligands was carried out in a stereoselective manner using a Reformatskii-Claisen reaction as the key step. Optically active ligands HIV-1LAI were converted to protease inhibitors. Two of these inhibitors (3 and 4) exhibited HIV-1 protease inhibitory Ki’s in picomolar range. Both inhibitors showed very potent antiviral activity with EC50 values of 0.8 nM and 3.1 nM respectively against the laboratory strain HIV-1LAI. Both inhibitors exhibited improved lipophilicity profiles compared to darunavir. Also, both inhibitors showed much improved blood-brain-barrier permeability in an in vitro model. A high resolution X-ray structure of inhibitor 4-bound HIV-1 protease was determined. The X-ray structure revealed that fluoro ligand makes extensive interactions with the HIV-1 protease S2 subsite, including hydrogen-bonding interactions with the protease backbone atoms. Also, both fluorine atoms on the bis-THF ligand formed strong interactions with the flap Gly48 carbonyl oxygen.
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影响因子：
1.8
作者：
FUJITA, K;NAKAI, H;OHNO, M
通讯作者：
OHNO, M
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.6
作者：
Ghosh, AK;Leshchenko, S;Noetzel, M
通讯作者：
Noetzel, M
影响因子：
3.5
作者：
Ghosh, Arun K.;Dawson, Zachary L.;Mitsuya, Hiroaki
通讯作者：
Mitsuya, Hiroaki
DOI：
10.1107/s0907444903008126
发表时间：
2003-07-01
影响因子：
2.2
作者：
Potterton, E;Briggs, P;Dodson, E
通讯作者：
Dodson, E