Inhibitors of angiotensin-converting enzyme containing a tetrahedral arsenic atom

Abstract

A series of tetrahedral oxo acids of Group VA and VIA elements and of silicon and boron were examined as inhibitors of angiotensin-converting enzyme. Arsenate is a competitive inhibitor with a Ki of 27 +/- 1 mM, at least 10-fold more potent than phosphate. Dimethylarsinate is a competitive inhibitor with a Ki of 70 +/- 9 mM, 2-fold more potent than dimethylphosphinate. Oxo acids of boron, silicon, antimony, sulphur and selenium are not inhibitors. On the basis of these results and the strong inhibition of this zinc metallopeptidase by substrate analogues containing a tetrahedral phosphorus atom, two substrate analogues containing a tetrahedral arsenic atom were prepared. 2-Arsonoacetyl-L-proline is a competitive inhibitor with a Ki of 18 +/- 7 mM, more than 2000-fold weaker than that of its phosphorus analogue 2-phosphonoacetyl-L-proline. 4-Arsono-2-benzylbutanoic acid is a mixed inhibitor with a Ki of 0.5 +/- 0.2 mM, indistinguishable in potency from its phosphorus analogue 2-benzyl-4-phosphonobutanoic acid.

Arsenic Binding to Proteins

“…These enzymes include phosphorylases, 363−368 phosphatases, 335,348,369−375 phosphoenolpyruvate mutase, 376 glycerol-3-phosphate dehydrogenase, 377 adenylate kinase, 378 enolase, 379 ethanolamine-phosphate cytidylytransferase, 380 triosephosphate isomerase, 381−383 ornithine carbamoyltransferase, 384,385 acetyl esterase, 304 chymotrypsin, 305,386 subtilisin, 305,386 and angiotensin-converting enzyme. 387 Ubiquitin, which has esterase, carbonic anhydrase, and phosphatase activities, was also inhibited by arsenate. 388 The majority of the enzymes mentioned above fall into the category of serine hydrolases.…”

Silanediols: A New Class of Potent Protease Inhibitors

“…[4,5] A dialkylsilanediol 5 [6,7] should be an isosteric analogue of the tetrahedral hydrolysis intermediate 4 of a peptide amide 3: The silicon atom of a silanediol is most stable in a tetrahedral configuration, and the hydroxyl groups are excellent hydrogen bond donors and acceptors. [8,9] Nevertheless, previous attempts to inhibit hydrolases with relatively simple silanediols [10] and silanetriols [11] found them to be inactive. Here we report the first synthesis of a silanediol-based dipeptide analogue and the discovery that these compounds can be potent inhibitors of the metalloproteases and, therefore, therapeutically important target molecules for medicinal chemistry.…”

Synthesis and structural study of precursors of novel methylsilanediols by IR and Raman spectroscopies, single-crystal X-ray diffraction and DFT calculations

“…The gem-silanediol group is most stable in its tetrahedral configuration than the corresponding geminal carbinol that readily undergo dehydration and, therefore, interaction with active site of protease is favored through hydroxyl groups which are excellent hydrogen bond donors and acceptors [5][6][7]. Nevertheless, previous attempts to inhibit hydrolases with relatively simple silanediols found them to be inactive [8]. This may be attributed to the fact that dialkylsilanediols with small side chains are prone to fast polymerization while steric effects of the bulky groups prevent silanediols from this process through the screening of OH groups.…”