title: Molecular modeling, design, synthesis, and biological evaluation of novel 3',4'-dicamphanoyl-(+)-cis-khellactone (DCK) analogs as potent anti-HIV agents.
abstract: Our current studies aimed at developing new potential anti-AIDS drug candidates have focused on the design and synthesis of new DCK analogs with improved molecular water solubility. Based on the structures and biodata of previous DCK analogs, 3D-QSAR studies have been performed which resulted in two reliable computational models, CoMFA and CoMSIA, with r(2) values of 0.995 and 0.987, and q(2) values of 0.662 and 0.657, respectively. In accord with these 3D-QSAR models, 15 new DCK analogs with polar functional groups at the 3-position were subsequently designed, synthesized, and evaluated against HIV-1 replication in H9 and MT4 cell lines. New DCK analogs 3b, 3c, 4b, 4c, 6a, 7c, and 9a showed promising potency with EC(50) values ranging from 0.09 to 0.0002 microM in both assays. Meanwhile, these promising compounds also showed a wide range of predicted logP values from 0.90 to 5.19, which increased the probability of identifying anti-HIV drug candidates from this class of compounds for clinical trials. Furthermore, both experimental and predicted values matched well, corroborating the reliability of the established 3D-QSAR models.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, China. khlee@email.unc.edu
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Zhao
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Chen
authors.forename: Bo-Tao
authors.initials: BT
authors.lastname: Fan
authors.forename: Xian-Hong
authors.initials: XH
authors.lastname: Chen
authors.forename: Jian-Zhou
authors.initials: JZ
authors.lastname: Ma
authors.forename: Jing-Yun
authors.initials: JY
authors.lastname: Li
authors.forename: Zhuo-Yi
authors.initials: ZY
authors.lastname: Bao
authors.forename: Zhaowen
authors.initials: Z
authors.lastname: Lo
authors.forename: Donglei
authors.initials: D
authors.lastname: Yu
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003374:Coumarins