title: Synthesis and evaluation of vinyl sulfones as caspase-3 inhibitors. A structure-activity study.
abstract: The first structure-activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P(1), as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH=CH-SO(2)Me was the most potent inhibitor of caspase-3 in the series, with a IC(50) of 29 microM and a second-order rate constant of inactivation, k(inact)/K(i), of 1.5 M(-1) s(-1). Computational studies suggest that the second amino acid occupies position S(3) of the enzyme. In addition, Fmoc-Val-Asp-trans-CH=CH-SO(2)Ph was inactive for caspase-7 for the tested concentrations.
authors.affiliation: Medicinal Chemistry, iMed.UL, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-019 Lisboa, Portugal.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Newton
authors.forename: Paulo M C
authors.initials: PM
authors.lastname: Glória
authors.forename: Lídia M
authors.initials: LM
authors.lastname: Gonçalves
authors.forename: Daniel J V A
authors.initials: DJ
authors.lastname: dos Santos
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.forename: Maria M M
authors.initials: MM
authors.lastname: Santos
mesh_terms: D053148:Caspase 3 / Q000737:chemistry; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D013450:Sulfones; C009873:divinyl sulfone; D053148:Caspase 3