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-khellactone (3-Cyanomethyl-4-methyl-DCK)

• Published in: Journal of medicinal chemistry Vol. 51; no. 24; pp. 7689 - 7696
• Main Authors: Xie, Lan, Guo, Huan-Fang, Lu, Hong, Zhuang, Xiao-Mei, Zhang, An-Ming, Wu, Gang, Ruan, Jin-Xiu, Zhou, Ting, Yu, Donglei, Qian, Keduo, Lee, Kuo-Hsiung, Jiang, Shibo
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.12.2008; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Area Under Curve; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Chemistry, Medicinal; Chemistry, Pharmaceutical - methods; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; Drug Design; Drug Evaluation, Preclinical; HIV-1 - metabolism; Humans; Life Sciences & Biomedicine; Male; Medical sciences; Models, Chemical; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Science & Technology; DESIGN; CD4; REVERSE-TRANSCRIPTASE INHIBITORS; CORECEPTOR; AIDS AGENTS; INFECTION; DRUG-RESISTANCE; IDENTIFICATION; DERIVATIVES; Enantiomer(+); Nitrile; Intravenous administration; Rat; HIV-1 virus; Coumarine derivatives; Preclinical trial; Optimization; Antiviral; Chemical synthesis; Terpenoid; Rodentia; Oral administration; Retroviridae; Lactone; Lentivirus; In vitro; Biological activity; Cis stereoisomer; Virus; In vivo; Vertebrata; Mammalia; Animal; Monoterpene; Human immunodeficiency virus; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8003009

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.