Development of cell-active non-peptidyl inhibitors of cysteine cathepsins

Dibyendu Dana; Anibal R. Davalos; Shatarupa De; Pratikkumar Rathod; Ranjith K. Gamage; Juliana Huestis; Nisar Afzal; Yuriy Zavlanov; Suneeta S. Paroly; Susan A. Rotenberg; Gopal Subramaniam; Kevin J. Mark; Emmanuel J. Chang; Sanjai Kumar

doi:10.1016/j.bmc.2013.03.062

Development of cell-active non-peptidyl inhibitors of cysteine cathepsins

Dibyendu Dana, Anibal R. Davalos, Shatarupa De, Pratikkumar Rathod, Ranjith K. Gamage, Juliana Huestis, Nisar Afzal, Yuriy Zavlanov, Suneeta S. Paroly, Susan A. Rotenberg, Gopal Subramaniam, Kevin J. Mark, Emmanuel J. Chang, Sanjai Kumar

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Cysteine cathepsins are an important class of enzymes that coordinate a variety of important cellular processes, and are implicated in various types of human diseases. However, small molecule inhibitors that are cell-permeable and non-peptidyl in nature are scarcely available. Herein the synthesis and development of sulfonyloxiranes as covalent inhibitors of cysteine cathepsins are reported. From a library of compounds, compound 5 is identified as a selective inhibitor of cysteine cathepsins. Live cell imaging and immunocytochemistry of metastatic human breast carcinoma MDA-MB-231 cells document the efficacy of compound 5 in inhibiting cysteine cathepsin activity in living cells. A cell-motility assay demonstrates that compound 5 is effective in mitigating the cell-migratory potential of highly metastatic breast carcinoma MDA-MB-231 cells.

Original language	English (US)
Pages (from-to)	2975-2987
Number of pages	13
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	11
DOIs	https://doi.org/10.1016/j.bmc.2013.03.062
State	Published - Jun 1 2013

Bibliographical note

Funding Information:
The authors wish to gratefully acknowledge the funding support provided by the PSC-CUNY Research Award Program , and Queensborough Community College (QCC)/Queens College NSF-STEP and NIH Bridges programs .

Keywords

Cancer metastasis
Cathepsin inhibitor
Cell migration
Cysteine protease inhibitor
Sulfonyloxiranes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Development of cell-active non-peptidyl inhibitors of cysteine cathepsins",

abstract = "Cysteine cathepsins are an important class of enzymes that coordinate a variety of important cellular processes, and are implicated in various types of human diseases. However, small molecule inhibitors that are cell-permeable and non-peptidyl in nature are scarcely available. Herein the synthesis and development of sulfonyloxiranes as covalent inhibitors of cysteine cathepsins are reported. From a library of compounds, compound 5 is identified as a selective inhibitor of cysteine cathepsins. Live cell imaging and immunocytochemistry of metastatic human breast carcinoma MDA-MB-231 cells document the efficacy of compound 5 in inhibiting cysteine cathepsin activity in living cells. A cell-motility assay demonstrates that compound 5 is effective in mitigating the cell-migratory potential of highly metastatic breast carcinoma MDA-MB-231 cells.",

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AU - Dana, Dibyendu

AU - Davalos, Anibal R.

AU - De, Shatarupa

AU - Rathod, Pratikkumar

AU - Gamage, Ranjith K.

AU - Huestis, Juliana

AU - Afzal, Nisar

AU - Zavlanov, Yuriy

AU - Paroly, Suneeta S.

AU - Rotenberg, Susan A.

AU - Subramaniam, Gopal

AU - Mark, Kevin J.

AU - Chang, Emmanuel J.

AU - Kumar, Sanjai

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PY - 2013/6/1

Y1 - 2013/6/1

N2 - Cysteine cathepsins are an important class of enzymes that coordinate a variety of important cellular processes, and are implicated in various types of human diseases. However, small molecule inhibitors that are cell-permeable and non-peptidyl in nature are scarcely available. Herein the synthesis and development of sulfonyloxiranes as covalent inhibitors of cysteine cathepsins are reported. From a library of compounds, compound 5 is identified as a selective inhibitor of cysteine cathepsins. Live cell imaging and immunocytochemistry of metastatic human breast carcinoma MDA-MB-231 cells document the efficacy of compound 5 in inhibiting cysteine cathepsin activity in living cells. A cell-motility assay demonstrates that compound 5 is effective in mitigating the cell-migratory potential of highly metastatic breast carcinoma MDA-MB-231 cells.

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KW - Cell migration

KW - Cysteine protease inhibitor

KW - Sulfonyloxiranes

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Development of cell-active non-peptidyl inhibitors of cysteine cathepsins

Abstract

Bibliographical note

Keywords

UN SDGs

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