Benzamidomethaneboronic acid: synthesis and inhibition of chymotrypsin.
Benzamidomethaneboronic acid (2) has been synthesized unambiguously from the reaction of dibutyl iodomethaneboronate and N-lithiohexamethyldisilazane to form dibutyl [bis(trimethylsilyl)amino]methaneboronate (4), which was desilylated, benzoylated, and hydrolyzed to 2. It has been shown that 2 is a strong competitive inhibitor of alpha-chymotrypsin (Ki = 8.1 X 10(-6) M, pH 7.5). The reaction product from dibutyl iodomethaneboronate and sodiobenzamide, previously shown to be a potent inhibitor of chymotrypsin, was shown by this work to be O-linked isomer, benzimidoxy-methaneboronic acid (3). The pH-Ki profile over the pH range 6.5-9.5 was consistent with the formation of an enzyme-inhibitor complex which resembled the metastable tetrahedral reaction intermediates occurring during acylation and deacylation of chymotrypsin-catalyzed hydrolysis.
D000215:Acylation; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D017646:Organosilicon Compounds; D012825:Silicon
D001896:Boron Compounds; D017646:Organosilicon Compounds; C042865:dibutyl iodomethaneboronate; C042863:benzamidomethaneboronic acid; D002918:Chymotrypsin; C024548:hexamethylsilazane; D012825:Silicon