title: 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).
abstract: 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.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China. lanxieshi@yahoo.com
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
authors.forename: Huan-Fang
authors.initials: HF
authors.lastname: Guo
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Zhuang
authors.forename: An-Ming
authors.initials: AM
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Jin-Xiu
authors.initials: JX
authors.lastname: Ruan
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Donglei
authors.initials: D
authors.lastname: Yu
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D019540:Area Under Curve; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D008297:Male; D008956:Models, Chemical; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C534490:3-cyanomethyl-4-methyl-3',4'-di-O-camphanoylkhellactone; D019380:Anti-HIV Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003374:Coumarins; C520900:khellactone