Active Site Ring-Opening of a Thiirane Moiety and Picomolar Inhibition of Gelatinases

被引：45

作者：

Forbes, Christopher ^{[1
,2
]}

Shi, Qicun ^{[1
,2
]}

Fisher, Jed F. ^{[1
,2
]}

Lee, Mijoon ^{[1
,2
]}

Hesek, Dusan ^{[1
,2
]}

Llarrull, Leticia I. ^{[1
,2
]}

Toth, Marta ^{[1
,2
]}

Gossing, Michael ^{[1
,2
]}

Fridman, Rafael ^{[3
,4
]}

Mobashery, Shahriar ^{[1
,2
]}

机构：

[1] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA

[2] Univ Notre Dame, Walther Canc Res Ctr, Notre Dame, IN 46556 USA

[3] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA

[4] Karmanos Canc Inst, Proteases & Canc Program, Detroit, MI 48201 USA

来源：

CHEMICAL BIOLOGY & DRUG DESIGN | 2009年 / 74卷 / 06期

基金：

美国国家卫生研究院;

关键词：

latent thiolate; thiirane; tight-binding inhibition; zinc protease; MATRIX-METALLOPROTEINASE INHIBITORS; RECEPTOR-STIMULATED APOPTOSIS; MECHANISM-BASED INHIBITION; SELECTIVE MMP INHIBITORS; CARBOXYPEPTIDASE-A; CANCER CELLS; ACTIVATION; INVASION; MATRIX-METALLOPROTEINASE-9; POTENT;

D O I：

10.1111/j.1747-0285.2009.00881.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

(+/-)-2-[(4-Phenoxyphenylsulfonyl)methyl]thiirane 1 is a potent and selective mechanism-based inhibitor of the gelatinase sub-class of the zinc-dependent matrix metalloproteinase family. Inhibitor 1 has excellent activity in in vivo models of gelatinase-dependent disease. We demonstrate that the mechanism of inhibition is a rate-limiting gelatinase-catalyzed thiolate generation via deprotonation adjacent to the thiirane, with concomitant thiirane opening. A corollary to this mechanism is the prediction that thiol-containing structures, related to thiirane-opened 1, will possess potent matrix metalloproteinase inhibitory activity. This prediction was validated by the synthesis of the product of this enzyme-catalyzed reaction on 1, which exhibited a remarkable K-i of 530 pm against matrix metalloproteinase-2. Thiirane 1 acts as a caged thiol, unmasked selectively in the active sites of gelatinases. This mechanism is unprecedented in the substantial literature on inhibition of zinc-dependent hydrolases.

引用

页码：527 / 534

页数：8

共 51 条

[1]

Ethanol-induced in vitro invasion of breast cancer cells:: The contribution of MMP-2 by fibroblasts [J].

Aye, MM ;

Ma, CL ;

Lin, H ;

Bower, KA ;

Wiggins, RC ;

Luo, J .

INTERNATIONAL JOURNAL OF CANCER, 2004, 112 (05) :738-746

[2]

Potent and selective mechanism-based inhibition of gelatinases [J].

Brown, S ;

Bernardo, MM ;

Li, ZH ;

Kotra, LP ;

Tanaka, Y ;

Fridman, R ;

Mobashery, S .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2000, 122 (28) :6799-6800

[3]

The regulation of matrix metalloproteinases and their inhibitors [J].

Clark, Ian A. ;

Swingler, Tracey E. ;

Sampieri, Clara L. ;

Edwards, Dylan R. .

INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2008, 40 (6-7) :1362-1378

[4]

Copeland R., 2005, EVALUATION ENZYME IN, V1st

[5]

Computational investigation of irreversible inactivation of the zinc-dependent protease carboxypeptidase A [J].

Cross, JB ;

Vreven, T ;

Meroueh, SO ;

Mobashery, S ;

Schlegel, HB .

JOURNAL OF PHYSICAL CHEMISTRY B, 2005, 109 (10) :4761-4769

[6]

Discovery of a novel series of selective MMP inhibitors:: Identification of the γ-sulfone-thiols [J].

Freskos, JN ;

Mischke, BV ;

DeCrescenzo, GA ;

Heintz, R ;

Getman, DP ;

Howard, SC ;

Kishore, NN ;

McDonald, JJ ;

Munie, GE ;

Rangwala, S ;

Swearingen, CA ;

Voliva, C ;

Welsch, DJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (07) :943-948

[7]

Synthesis and identification of conformationally constrained selective MMP inhibitors [J].

Freskos, JN ;

McDonald, JJ ;

Mischke, BV ;

Mullins, PB ;

Shieh, HS ;

Stegeman, RA ;

Stevens, AM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (13) :1757-1760

[8]

A comparative study on the experimentally derived electron densities of three protease inhibitor model compounds [J].

Grabowsky, Simon ;

Pfeuffer, Thomas ;

Morgenroth, Wolfgang ;

Paulmann, Carsten ;

Schirmeister, Tanja ;

Luger, Peter .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2008, 6 (13) :2295-2307

[9]

A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia [J].

Gu, ZZ ;

Cui, J ;

Brown, S ;

Fridman, R ;

Mobashery, S ;

Strongin, AY ;

Lipton, SA .

JOURNAL OF NEUROSCIENCE, 2005, 25 (27) :6401-6408

[10]

Matrix metalloproteinases are required for retinal ganglion cell axon guidance at select decision points [J].

Hehr, CL ;

Hocking, JC ;

McFarlane, S .

DEVELOPMENT, 2005, 132 (15) :3371-3379

← 1 2 3 4 5 6 →