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.
authors.affiliation: Department of Chemistry and Biochemistry, Queens College and the Graduate Center of The City University of New York, Queens, NY 11367-1597, USA.
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Dana
authors.forename: Anibal R
authors.initials: AR
authors.lastname: Davalos
authors.forename: Shatarupa
authors.initials: S
authors.lastname: De
authors.forename: Pratikkumar
authors.initials: P
authors.lastname: Rathod
authors.forename: Ranjith K
authors.initials: RK
authors.lastname: Gamage
authors.forename: Juliana
authors.initials: J
authors.lastname: Huestis
authors.forename: Nisar
authors.initials: N
authors.lastname: Afzal
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Zavlanov
authors.forename: Suneeta S
authors.initials: SS
authors.lastname: Paroly
authors.forename: Susan A
authors.initials: SA
authors.lastname: Rotenberg
authors.forename: Gopal
authors.initials: G
authors.lastname: Subramaniam
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Mark
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Chang
authors.forename: Sanjai
authors.initials: S
authors.lastname: Kumar
mesh_terms: D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004852:Epoxy Compounds; D013450:Sulfones; D002403:Cathepsins; D003545:Cysteine