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)

In prior investigation, we discovered that (3'R,4'R)-3-cyanomethyl-4-methyl-3',4'-di-O-(S)-camphanoly-(+)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 phamacokinetic 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 its a promising anti-HIV agent for development as a clinical trial candidate.