Silicon-based metalloprotease inhibitors: Synthesis and evaluation of silanol and silanediol peptide analogues as inhibitors of angiotensin-converting enzyme

被引:157
作者
Mutahi, MW [1 ]
Nittoli, T [1 ]
Guo, LX [1 ]
Sieburth, SM [1 ]
机构
[1] Temple Univ, Dept Chem, Philadelphia, PA 19122 USA
关键词
D O I
10.1021/ja026158w
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Silanols are best known as unstable precursors of siloxane (silicone) polymers, substances generally considered stable and inert, but have the potential to mimic a hydrated carbonyl and inhibit protease enzymes. While previous testing of simple silanediol and silanetriol species as inhibitors of hydrolase enzymes found them ineffective, this study reports polypeptide mimics with a central methylsilanol [SiMeOH] or silanediol [Si(OH)(2)] group and their assessment as effective transition state analogue inhibitors of the well-studied metalloprotease angiotensin-converting enzyme (ACE). Central to the synthesis strategy, phenylsilanes were employed as acid-hydrolyzable precursors of the silanol group. The N-benzoyl Leu[SiMeOH]-Gly benzyl amides proved to be stable and readily characterized. In contrast, the Leu-[Si(OH)(2)]Gly structure was difficult to characterize, possibly because of self-association. Capping the silanediol with chlorotrimethylsilane gave a well-defined trisiloxane, demonstrating that the silanediol was monomeric. The Leu-[Si]-Gly structures were converted to Leu-[Si]-Ala analogues by enolate alkylation. Coupling of the silanol precursors with proline tert-butyl ester gave N-benzoyl Leu-[Si]-Gly-Pro and N-benzoyl Leu[Si]-Ala-Pro tripeptide analogues. Treatment of these with triflic acid formed the corresponding methylsilanols and silanediols, all of which were monomeric. The silanediol tripeptide mimics inhibited ACE with IC50 values as low as 14 nM. Methylsilanols, in contrast, were poor inhibitors, with IC50 values above 3000 nM. These data, including comparisons with inhibition data from carbon analogues, are consistent with binding of the silanediols by chelation of the ACE active site zinc, whereas the methylsilanols ligate poorly.
引用
收藏
页码:7363 / 7375
页数:13
相关论文
共 113 条
[1]   Host-guest chemistry in a urea matrix:: Catalytic and selective oxidation of triorganosilanes to the corresponding silanols by methyltrioxorhenium and the urea/hydrogen peroxide adduct [J].
Adam, W ;
Mitchell, CM ;
Saha-Möller, CR ;
Weichold, O .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1999, 121 (10) :2097-2103
[2]   Synthesis, structure-activity relationships, and pharmacokinetic profiles of nonpeptidic α-keto heterocycles as novel inhibitors of human chymase [J].
Akahoshi, F ;
Ashimori, A ;
Sakashita, H ;
Yoshimura, T ;
Imada, T ;
Nakajima, M ;
Mitsutomi, N ;
Kuwahara, S ;
Ohtsuka, T ;
Fukaya, C ;
Miyazaki, M ;
Nakamura, N .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (08) :1286-1296
[3]   DERIVATIVES OF THE POTENT ANGIOTENSIN CONVERTING ENZYME-INHIBITOR 5(S)-BENZAMIDO-4-OXO-6-PHENYLHEXANOYL-L-PROLINE - EFFECT OF CHANGES AT POSITION-2 AND POSITION-5 OF THE HEXANOIC ACID PORTION [J].
ALMQUIST, RG ;
CRASE, J ;
JENNINGSWHITE, C ;
MEYER, RF ;
HOEFLE, ML ;
SMITH, RD ;
ESSENBURG, AD ;
KAPLAN, HR .
JOURNAL OF MEDICINAL CHEMISTRY, 1982, 25 (11) :1292-1299
[4]   Free-radical cyclization in the synthesis of a 1-aza-5-silabicyclo[5.2.0]nonan-9-one, a silicon-containing beta-lactam [J].
Altamura, M ;
Giammaruco, M ;
Taddei, M ;
Ulivi, P .
JOURNAL OF ORGANIC CHEMISTRY, 1995, 60 (26) :8403-8406
[5]  
AMIDES, 1999, J ORG CHEM, V64, P6005
[6]   SYNTHESIS, ANTITUMOR-ACTIVITY, AND CHEMICAL-PROPERTIES OF SILAPLATIN AND RELATED PLATINUM(II) AND PLATINUM(IV) COMPLEXES DERIVED FROM BETA-SILYL AMINES [J].
ANDERSON, WK ;
KASLIWAL, R ;
HOUSTON, DM ;
WANG, YS ;
NARAYANAN, VL ;
HAUGWITZ, RD ;
PLOWMAN, J .
JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (19) :3789-3797
[7]  
Apeloig Y., 1989, CHEM ORGANIC SILICON, P57
[8]  
ASLANOV LA, 1979, J STRUCT CHEM+, V20, P646
[9]  
Auld DS, 1997, STRUCT BOND, V89, P29
[10]  
BARCZA S, 1988, SILICON CHEMISTRY, P135