Indium-mediated atom-transfer and reductive radical cyclizations of iodoalkynes: synthesis and biological evaluation of HIV-protease inhibitors.
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.
Yanada
Reiko
R
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ryanada@pharm.kyoto-u.ac.jp
Koh
Yasuhiro
Y
Nishimori
Nobuaki
N
Matsumura
Akira
A
Obika
Shingo
S
Mitsuya
Hiroaki
H
Fujii
Nobutaka
N
Takemoto
Yoshiji
Y
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
D017320:HIV Protease Inhibitors; D006847:Hydrocarbons, Iodinated; D007204:Indium