title: Indium-mediated atom-transfer and reductive radical cyclizations of iodoalkynes: synthesis and biological evaluation of HIV-protease inhibitors.
abstract: Novel indium-mediated radical cyclization reactions of aliphatic iodoalkynes have been studied. Treatment of iodoalkynes with a catalytic amount of In (0.1 equiv) and I(2) (0.05 equiv) promotes atom-transfer 5-exo cyclization to give five-membered alkenyl iodides. In contrast, reaction with In (2 equiv) and I(2) (1 equiv) yields reductive 5-exo cyclization products via the same 5-exo cyclization. Both processes are most likely initiated by low-valent indium species. To demonstrate versatility of these reactions, optically active HIV protease inhibitors were synthesized by this reductive cyclization method. Among them, several products, which contain a hydroxyethylamine dipeptide isostere as a transition state-mimicking substructure, proved to possess potent activity (IC(50) = 5-39 nM) against a wide spectrum of HIV strains, including multidrug-resistant variants.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ryanada@pharm.kyoto-u.ac.jp
authors.forename: Reiko
authors.initials: R
authors.lastname: Yanada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Nishimori
authors.forename: Akira
authors.initials: A
authors.lastname: Matsumura
authors.forename: Shingo
authors.initials: S
authors.lastname: Obika
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Takemoto
mesh_terms: D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D015195:Drug Design; D024921:Drug Resistance, Multiple, Viral; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006847:Hydrocarbons, Iodinated / Q000138:chemical synthesis* / Q000494:pharmacology; D007204:Indium / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D006847:Hydrocarbons, Iodinated; D007204:Indium