title: 1,2,5-Thiadiazolidin-3-one 1,1 dioxide: a powerful scaffold for probing the S' subsites of (chymo)trypsin-like serine proteases.
abstract: The 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold (I) embodies a motif that allows it to dock to the active site of (chymo)trypsin-like proteases in a predictable and substrate-like fashion. Consequently, inhibitors derived from this heterocyclic scaffold interact with both the S and S' subsites of an enzyme. Exploitation of binding interactions with both the S and S' subsites of a target enzyme may lead to compounds with greatly enhanced enzyme selectivity and inhibitory potency. This preliminary report describes the use of a series of compounds having the heterocyclic scaffold linked to various amino acids to probe the S' subsites of human leukocyte elastase (HLE), proteinase 3 (PR 3), and cathepsin G (Cat G). For comparative purposes, a series of compounds derived from a related scaffold, isothiazolidin-3-one 1,1 dioxide (II), was also generated. Several of the compounds were found to be highly potent and selective time-dependent inhibitors of HLE, PR 3, and Cat G.
authors.affiliation: Department of Chemistry, Wichita State University, Kansas 67260, USA. groutas@wsuhub.uc.twsu.edu
authors.forename: W C
authors.initials: WC
authors.lastname: Groutas
authors.forename: J B
authors.initials: JB
authors.lastname: Epp
authors.forename: R
authors.initials: R
authors.lastname: Kuang
authors.forename: S
authors.initials: S
authors.lastname: Ruan
authors.forename: L S
authors.initials: LS
authors.lastname: Chong
authors.forename: R
authors.initials: R
authors.lastname: Venkataraman
authors.forename: J
authors.initials: J
authors.lastname: Tu
authors.forename: S
authors.initials: S
authors.lastname: He
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: Q
authors.initials: Q
authors.lastname: Fu
authors.forename: Y H
authors.initials: YH
authors.lastname: Li
authors.forename: T M
authors.initials: TM
authors.lastname: Truong
authors.forename: N T
authors.initials: NT
authors.lastname: Vu
mesh_terms: D056649:Cathepsin G; D002403:Cathepsins / Q000737:chemistry / Q000378:metabolism; D002918:Chymotrypsin / Q000737:chemistry*; D003499:Cyclic S-Oxides / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D015335:Molecular Probes / Q000737:chemistry*; D053146:Myeloblastin; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D013696:Temperature; D013844:Thiazoles / Q000737:chemistry*; D013997:Time Factors
chemical_list: C428430:1,2,5-thiadiazolidin-3-one 1,1-dioxide; D003499:Cyclic S-Oxides; D015335:Molecular Probes; D013844:Thiazoles; D002403:Cathepsins; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D053146:Myeloblastin