Solid-phase synthesis of HTLV-1 protease inhibitors containing hydroxyethylamine dipeptide isostere.
An efficient method has been developed for the first solid-phase synthesis of HTLV-1 protease inhibitors that contain hydroxyethylamine isostere as a transition-state mimetic. The synthetic procedure was designed to allow the evaluation of stereostructure-activity relationships at the scissile site. All the possible configurations at the hydroxy- and side chain-bearing asymmetric centers of the isostere were constructed by an ester-derived asymmetric aldol reaction. Each inhibitor containing the isostere backbone was synthesized on solid support by using the newly developed succinate ester linker. The configuration at the hydroxy- and side chain-bearing asymmetric center showed remarkable effects on the inhibitory activity; the K(i) value changed with approximately 2 orders of magnitude. The described approach enables an efficient preparation of the inhibitors containing secondary alcohol as a transition-state mimetic.
Akaji
Kenichi
K
Institute for Protein Research, Osaka University, Osaka 565-0871, Japan. akaji@protein.osaka-u.ac.jp
Teruya
Kenta
K
Aimoto
Saburo
S
D000588:Amines / Q000737:chemistry* / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000588:Amines; D004151:Dipeptides; D017320:HIV Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C079711:HTLV-1 protease