新型烯基二芳基甲烷HIV-1非核苷类逆转录酶抑制剂的合成、抗HIV活性及代谢稳定性
Synthesis, anti-HIV activity, and metabolic stability of new alkenyldiarylmethane HIV-1 non-nucleoside reverse transcriptase inhibitors.
作者信息
Deng Bo-Liang, Hartman Tracy L, Buckheit Robert W, Pannecouque Christophe, De Clercq Erik, Fanwick Phillip E, Cushman Mark
机构信息
Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
出版信息
J Med Chem. 2005 Sep 22;48(19):6140-55. doi: 10.1021/jm050452s.
Abstract
Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are part of the combination therapy currently used to treat HIV infection. Based on analogy with known HIV-1 NNRT inhibitors, 18 novel alkenyldiarylmethanes (ADAMs) containing 5-chloro-2-methoxyphenyl, 3-cyanophenyl, or 3-fluoro-5-trifluoromethylphenyl groups were synthesized and evaluated as HIV inhibitors. Their stabilities in rat plasma have also been investigated. Although introducing 5-chloro-2-methoxyphenyl or 3-fluoro-5-trifluoromethylphenyl groups into alkenyldiarylmethanes does not maintain the antiviral potency, the structural modification of alkenyldiarylmethanes with a 3-cyanophenyl substituent can be made without a large decrease in activity. The oxazolidinonyl group was introduced into the alkenyldiarylmethane framework and found to confer enhanced metabolic stability in rat plasma.
摘要
HIV-1逆转录酶非核苷抑制剂（NNRTIs）是目前用于治疗HIV感染的联合疗法的一部分。基于与已知HIV-1非核苷逆转录酶抑制剂的类比，合成了18种含有5-氯-2-甲氧基苯基、3-氰基苯基或3-氟-5-三氟甲基苯基的新型烯基二芳基甲烷（ADAMs），并将其作为HIV抑制剂进行评估。还研究了它们在大鼠血浆中的稳定性。虽然将5-氯-2-甲氧基苯基或3-氟-5-三氟甲基苯基引入烯基二芳基甲烷中不能维持抗病毒效力，但用3-氰基苯基取代基对烯基二芳基甲烷进行结构修饰时，活性不会大幅下降。将恶唑烷酮基引入烯基二芳基甲烷骨架中，发现其在大鼠血浆中具有更高的代谢稳定性。
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本文引用的文献
1
Processing of X-ray diffraction data collected in oscillation mode.振荡模式下收集的X射线衍射数据的处理。
Methods Enzymol. 1997;276:307-26. doi: 10.1016/S0076-6879(97)76066-X.
2
Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future.非核苷类逆转录酶抑制剂（NNRTIs）：过去、现在与未来
Chem Biodivers. 2004 Jan;1(1):44-64. doi: 10.1002/cbdv.200490012.
3
The mechanisms of the Stille reaction.施蒂勒反应的机制。
Angew Chem Int Ed Engl. 2004 Sep 13;43(36):4704-34. doi: 10.1002/anie.200300638.
4
Design, synthesis, anti-HIV activities, and metabolic stabilities of alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors.烯基二芳基甲烷（ADAM）非核苷类逆转录酶抑制剂的设计、合成、抗HIV活性及代谢稳定性
J Med Chem. 2004 Jun 3;47(12):3149-62. doi: 10.1021/jm049916x.
5
Novel benzophenones as non-nucleoside reverse transcriptase inhibitors of HIV-1.新型二苯甲酮类化合物作为HIV-1的非核苷类逆转录酶抑制剂
J Med Chem. 2004 Feb 26;47(5):1175-82. doi: 10.1021/jm030255y.
6
The 'apparent' hydrolysis of alkyl esters during electrospray ionization.电喷雾电离过程中烷基酯的“表观”水解
Rapid Commun Mass Spectrom. 2003;17(15):1703-8. doi: 10.1002/rcm.1104.
7
Palladium-catalyzed coupling reactions of aryl chlorides.芳基氯化物的钯催化偶联反应。
Angew Chem Int Ed Engl. 2002 Nov 15;41(22):4176-211. doi: 10.1002/1521-3773(20021115)41:22<4176::AID-ANIE4176>3.0.CO;2-U.
8
Metal-catalyzed hydrostannations.金属催化的氢化锡化反应。
Chem Rev. 2000 Aug 9;100(8):3257-82. doi: 10.1021/cr9902695.
9
Synthesis of alkenyldiarylmethane (ADAM) non-nucleoside HIV-1 reverse transcriptase inhibitors with non-identical aromatic rings.
Bioorg Med Chem. 2002 Feb;10(2):283-90. doi: 10.1016/s0968-0896(01)00282-6.
10
The biological effects of structural variation at the meta position of the aromatic rings and at the end of the alkenyl chain in the alkenyldiarylmethane series of non-nucleoside reverse transcriptase inhibitors.非核苷类逆转录酶抑制剂烯基二芳基甲烷系列中芳环间位和烯基链末端结构变异的生物学效应。
J Med Chem. 2001 Nov 22;44(24):4092-113. doi: 10.1021/jm010212m.
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