Silanediol inhibitors of angiotensin-converting enzyme. synthesis and evaluation of four diastereomers of Phe[Si]Ala dipeptide analoguesl
Silanediol inhibitors of angiotensin-converting enzyme. synthesis and evaluation of four diastereomers of Phe[Si]Ala dipeptide analoguesl
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DOI：
10.1021/jo048121v
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发表时间：
2005-07-22
影响因子：
3.6
通讯作者：
Sieburth, SM
中科院分区：
文献类型：
--
作者：
Kim, J;Hewitt, G;Sieburth, SM
Phe-Ala硅烷二醇二肽模拟物的四种立体异构体作为血管紧张素转化酶（ACE）抑制剂已被评价，并与Almquist等人报道的酮基抑制剂进行了比较。异构体的一个立体中心来自3-羟基-2-甲基丙酸甲酯的单个对映体，引入第二个立体中心后分离非对映体。通过中间体的X射线晶体学确定非对映体身份。三种硅烷二醇非对映体对ACE的抑制作用（IC 50 = 3.8-207 nM）与相应的非对映体酮（IC 50 = 1.0-46 nM）非常接近。第四种非对映异构体，对应于最低抑制性酮（IC 50 = 3200 nM），在硅烷二醇中表现出意想不到的抑制水平（IC 50 = 72 nM），表明与酶结合的替代模式。
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 (IC50 = 3.8-207 nM) closely paralleled that of the corresponding diastereomeric ketones (IC50 = 1.0-46 nM). The fourth diastereomer, corresponding to the least inhibitory ketone (IC50 = 3200 nM), exhibited an unexpected level of inhibition in the silanediol (IC50 = 72 nM), suggesting an alternative mode of binding to the enzyme.