A silanediol inhibitor of the metalloprotease thermolysin: synthesis and comparison with a phosphinic acid inhibitor |
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Authors: | Kim Jaeseung Sieburth Scott McN |
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Institution: | Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA. |
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Abstract: | A silanediol inhibitor of the metalloprotease thermolysin was prepared for comparison to a known phosphinic acid inhibitor, providing the first comparison of these second-row element based transition-state analogues. Inhibition of thermolysin by the silanediol (K(i) = 41 nM) was comparable to that of the phosphinic acid (K(i) = 10 nM) even though the silanediol is uncharged and thereby lacks the intrinsic Coulombic attraction of the phosphinate anion to the active-site zinc cation. This silanediol protease inhibitor is the least sterically encumbered example prepared to date and, therefore, the most prone toward polymerization. Hydrolysis of a difluorosilane intermediate to the silanediol leads cleanly to a monomeric product. |
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