ChemInform Abstract: Convenient Preparation of All Four Possible Stereoisomers of 2‐Benzyl‐ 3,4‐epoxybutanoic Acid, Pseudomechanism‐Based Inactivator for Carboxypeptidase A via α‐Chymotrypsin‐Catalyzed Hydrolysis.

Kim, Y. M.; Kim, Do Hyeong

doi:10.1002/chin.199718135

Cited by 2 publications

(3 citation statements)

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“…Epoxidation of the substituted 2-vinyl propanoate esters 25 provided the separable mixture of trans (26; major) and cis (27; minor) epoxides. 24 With the derivatives 26 in hand, the trans oxiranes 1, 5, 9, 13, 15, 17, 19, and 21 were obtained by treatment with lithium hydroxide or hydrogenolysis over Pd/C. However, treatment of derivatives 26 with thiourea, followed by hydrolysis afforded the corresponding cis thiiranes 4, 8, and 12.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

“…racemic α-substituted β,γ-unsaturated carboxylic acids were esterified as methyl or benzyl ester by standard methodologies. Epoxidation of the substituted 2-vinyl propanoate esters 25 provided the separable mixture of trans (26; major) and cis (27; minor) epoxides 24. With the derivatives 26 in hand, the trans oxiranes 1, 5, 9, 13, 15, 17, 19, and 21 were obtained by treatment with lithium hydroxide or hydrogenolysis over Pd/C.…”

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confidence: 99%

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Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library

Testero

Granados

Fernández

et al. 2017

ACS Med. Chem. Lett.

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Metallocarboxypeptidases (MCPs) are involved in many biological processes such as fibrinolysis or inflammation, development, Alzheimer's disease, and various types of cancer. We describe the synthesis and kinetic characterization of a focused library of 22 thiirane- and oxirane-based potential mechanism-based inhibitors, which led to discovery of an inhibitor for the human pro-carboxypeptidase A1. Our structural analyses show that the thiirane-based small-molecule inhibitor penetrates the barrier of the pro-domain to bind within the active site. This binding leads to a chemical reaction that covalently modifies the catalytic Glu270. These results highlight the importance of combined structural, biophysical, and biochemical evaluation of inhibitors in design strategies for the development of spectroscopically nonsilent probes as effective beacons for ,, and/or localization in clinical and industrial applications.

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

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confidence: 99%

Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library

Testero

Granados

Fernández

et al. 2017

ACS Med. Chem. Lett.

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“…In an effort to elucidate the minimal structural motifs for inhibition of carboxypeptidases by thiirane-based inhibitors, we turned to two examples from the literature. Compound 3 (2-benzyl-3,4-epithiobutanoic acid), as well as its oxirane version, 4 (2-benzyl)-3,4-epoxybutanoic acid), have been reported as mechanism-based inactivators of carboxypeptidase A (CPA) (31)(32)(33). An earlier structural determination of CPA in complex with oxirane 4 (34,35) has been reported, although the atomic coordinates have not been deposited.…”

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confidence: 99%

The X‐Ray Structure of Carboxypeptidase A Inhibited by a Thiirane Mechanism‐Based Inhibitor

et al. 2009

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The three-dimensional X-ray crystal structure of carboxypeptidase A, a zinc-dependent hydrolase, covalently modified by a mechanism-based thiirane inactivator, 2-benzyl-3,4-epithiobutanoic acid, has been solved to 1.38 Å resolution. The interaction of the thiirane moiety of the inhibitor with the active site zinc ion promotes its covalent modification of Glu-270 with the attendant opening of the thiirane ring. The crystal structure determination at high resolution allowed for the clear visualization of the covalent ester bond to the glutamate side chain. The newly generated thiol from the inhibitor binds to the catalytic zinc ion in a monodentate manner, inducing a change in the zinc ion geometry and coordination, while its benzyl group fits into the S1' specificity pocket of the enzyme. The inhibitor molecule is distorted at the position of the carbon atom that is involved in the ester bond linkage on one side and the zinc coordination on the other. This particular type of thiirane-based metalloprotease inhibitor is for the first time analyzed in complex to the target protease at high resolution and may be used as a general model for zinc-dependent proteases.Key words: M14 family of proteases, mechanism-based inactivation, metallopeptidase, thiirane, X-ray crystallography Metalloproteases from the M14 family (carboxypeptidases, CPs) are involved in many physiologic and pathological processes such as tissue organogenesis (1-3), acute pancreatitis (4,5), diabetes (6,7), inflammation (8,9), fibrinolysis (10,11), neurologic diseases (12), and cancer (13-16). Circulating forms of CP may be used as prognostic tools for the early detection of cancer and other diseases (17). The M14 family of proteases comprises an extended and complex array of zinc-dependent proteins with wide genomic distribution (18-20). They share with matrix metalloproteases (MMPs; e.g., gelatinases, collagenases, matrilysins, and stromelysins) a similar catalytic mechanism, whereby the catalytic zinc ion predisposes the substrate to turnover with the involvement of a conserved glutamate residue in the active site (21). Notwithstanding the shared features of their respective mechanisms, MMPs are endopeptidases, whereas CPs are exopeptidases that remove the C-terminal residues from peptide substrates.Most known small-molecule inhibitors of CPs are chelators of the active site zinc ion. These chelators are often non-discriminant, as their function hinges on coordination with metals. The limited selectivity among potent zinc chelators can be exemplified by thioldependent CP inhibitors, such as 1 (2-mercaptomethyl-3-guanidinoethylthiopropanoic acid, Plummer's inhibitor (22)), which was still found to inhibit other M14 proteases (23). A similar concern has been encountered in the development of MMP inhibitors with subtype selectivity (24). Mechanism-based inactivators ('suicide substrate' or 'k cat inactivator') exploit features of the catalytic mechanisms of the targetted enzymes (25). An innocuous agent is converted to the inhibitory species only wit...

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ChemInform Abstract: Convenient Preparation of All Four Possible Stereoisomers of 2‐Benzyl‐ 3,4‐epoxybutanoic Acid, Pseudomechanism‐Based Inactivator for Carboxypeptidase A via α‐Chymotrypsin‐Catalyzed Hydrolysis.

Cited by 2 publications

References 0 publications

Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library

Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library

The X‐Ray Structure of Carboxypeptidase A Inhibited by a Thiirane Mechanism‐Based Inhibitor

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