title: A new structural theme in C2-symmetric HIV-1 protease inhibitors: ortho-substituted P1/P1' side chains.
abstract: In this report, the rapid syntheses of 24 novel C2-symmetric HIV-1 protease inhibitors are described. Two ortho-iodobenzyloxy containing C-terminal duplicated inhibitors served as starting materials for microwave-enhanced palladium(0)-catalyzed carbon-carbon bond forming reactions (Suzuki, Sonogashira, Heck, and Negishi). Highly potent inhibitors equipped with ortho-functionalized P1/P1' side chains as the structural theme were identified. Computational efforts were applied to study the binding mode of this class of inhibitors and to establish structure-activity relationships. The overall orientation of the inhibitors in the active site was reproduced by docking which suggested three possible conformations of the P1/P1' groups of which two seem more plausible.
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Wannberg
authors.forename: Yogesh A
authors.initials: YA
authors.lastname: Sabnis
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002384:Catalysis; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry* / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008872:Microwaves; D008958:Models, Molecular; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
chemical_list: D000577:Amides; D017320:HIV Protease Inhibitors; D010165:Palladium; D016333:HIV Protease