INHIBITION OF THE SERINE PROTEASE CHYMOTRYPSIN BY A SILANEDIOL PEPTIDE MIMIC: ASYMMETRIC SYNTHESIS AND INHIBITION STUDIES

Abstract

Dialkylsilanediols are non-hydrolyzable analogs of the tetrahedral intermediate of amide hydrolysis and have shown outstanding inhibition of metallo and aspartic proteases. This research describes the synthesis and inhibition of the serine protease α- chymotrypsin by silanediol structures and the development of an efficient method to install the stereochemistry at the P1’ position of the inhibitor. In the first part, the silanediol 67 was synthesized as a potential α-chymotrypsin inhibitor, however it showed no inhibition activity at longer equilibration times with the enzyme, suggesting an instability and the need for modification in the inhibitor design. Changing Ac-leucine at P2 in 67 to the proline gave 47 and 66. Compounds 47 and 66 were good inhibitors of chymotrypsin with Ki values of 106±10nM and 65±10 nM respectively. The second part of the research concentrates on the development of an efficient method to install different substituents at the P1’ position with an emphasis on stereoselectivity. Two methods were developed. The first method used the 2-alkyl-1,3-butadiene such as 58 which, on cycloaddition with diphenyldichlorosilane forms a 2,5- dihydrosilole. Asymmetric hydroboration then sets the desired stereochemistry. This method suffered, however, from the absence of readily available 2-alkyl-1,3-dienes. The second method employed catalytic asymmetric intramolecular hydrosilylation of allyl silyl ethers 130, which sets the stereochemistry with up to 94% ee, using rhodium with a ferrotane ligand. This method provides a short and general method for installation of a broad range of alkyl groups at the P1’ position with high enantioselectivity.