Silanediol inhibitors of angiotensin-converting enzyme. Synthesis and evaluation of four diastereomers of Phe[Si]Ala dipeptide analogues.
Four stereoisomers of a Phe-Ala silanediol dipeptide mimic have been evaluated as inhibitors of angiotensin-converting enzyme (ACE) and compared to ketone-based inhibitors reported by Almquist et al. One stereogenic center of the isomers was derived from the individual enantiomers of methyl 3-hydroxy-2-methylpropionate, with separation of diastereomers after introduction of the second stereogenic center. The diastereomeric identities were established by X-ray crystallography of an intermediate. Inhibition of ACE by three of the silanediol diastereomers (IC(50) = 3.8-207 nM) closely paralleled that of the corresponding diastereomeric ketones (IC(50) = 1.0-46 nM). The fourth diastereomer, corresponding to the least inhibitory ketone (IC(50) = 3200 nM), exhibited an unexpected level of inhibition in the silanediol (IC(50) = 72 nM), suggesting an alternative mode of binding to the enzyme.
Kim
Jaeseung
J
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Hewitt
Gregory
G
Carroll
Patrick
P
Sieburth
Scott McN
SM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D011422:Propionates / Q000737:chemistry; D012821:Silanes / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D011422:Propionates; D012821:Silanes; C475536:silanediol; C039552:phenylalanylalanine