Design, synthesis, molecular modeling studies, and calpain inhibitory activity of novel alpha-ketoamides incorporating polar residues at the P1'-position.
A series of novel alpha-ketoamides incorporating stereoisomeric residues with different electronic properties at the P(1)'-position were synthesized to study the electronic requirements for inhibitor binding to the S(1)'-subsite of calpain I. The results of the study suggested the presence of an acidic amino acid residue at the S(1)'-subsite of calpain I. For example, ester 1a (Cbz-l-Leu-l-Phe-CO-d-Phe-OMe) was over 450-fold more potent than its carboxylic acid derivative 2a (Cbz-l-Leu-l-Phe-CO-d-Phe-OH). Additionally, amidino derivative 3a (Cbz-l-Leu-l-Phe-CONH-d-CH[C(NH)NH(2)]Bn) was about 6000-fold more potent than 2a. Furthermore, 4a (Cbz-l-Leu-l-Phe-CONHCH(2)Bn) was 12-fold less potent than its aza analogue 4b (Cbz-l-Leu-l-Phe-CONHNHBn). The results are consistent with the presence of an acidic amino acid residue at the S(1)'-subsite of calpain I. The acidic amino acid residue was found to be Glu261 via molecular modeling studies.
Donkor
Isaac O
IO
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. idonkor@utmem.edu
Han
Jie
J
Zheng
Xiaozhang
X
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D007659:Ketones; D002154:Calpain