Development and Preclinical Studies of Broad-Spectrum Anti-HIV Agent (3′R,4′R)-3-Cyanomethyl-4-methyl-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khell

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• 作者：Lan Xie ; Huan-Fang Guo ; Hong Lu ; Xiao-Mei Zhuang ; An-Ming Zhang ; Gang Wu ; Jin-Xiu Ruan ; Ting Zhou ; Donglei Yu ; Keduo Qian ; Kuo-Hsiung Lee ; Shibo Jiang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 25, 2008
• 年：2008
• 卷：51
• 期：24
• 页码：7689-7696
• 全文大小：198K
• 年卷期：v.51,no.24(December 25, 2008)
• ISSN：1520-4804

文摘

In prior investigation, we discovered that (3′R,4′R)-3-cyanomethyl-4-methyl-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (4, 3-cyanomethyl-4-methyl-DCK) showed promising anti-HIV activity. In these current studies, we developed and optimized successfully a practical 10-step synthesis for scale-up preparation to increase the overall yield of 4 from 7.8% to 32%. Furthermore, compound 4 exhibited broad-spectrum anti-HIV activity against wild-type and drug-resistant viral infection of CD4+ T cell lines as well as peripheral blood mononuclear cells by both laboratory-adapted and primary HIV-1 isolates with distinct subtypes and tropisms. Compound 4 was further subjected to in vitro and in vivo pharmacokinetic studies. These studies indicated that 4 has moderate cell permeability, moderate oral bioavailability, and low systemic clearance. These results suggest that 4 should be developed as a promising anti-HIV agent for development as a clinical trial candidate.