title: Aspartic vinyl sulfones: inhibitors of a caspase-3-dependent pathway.
abstract: In this article we describe an expanded structure-activity relationship study for vinyl sulfones as caspase-3 inhibitors, a topic virtually unexplored in the existing literature. Most remarkably, and to our surprise, tripeptidyl vinyl sulfones were not active for caspase-3, opposite to other examples described in literature for peptidyl vinyl sulfones as potent cysteine protease inhibitors of clan CA. Moreover, the caspase-3 inhibitory activity of vinyl sulfones using an in vitro assay was then confirmed using a yeast cell-based assay. The results show that Fmoc-protected vinyl sulfones containing only the Asp moiety are inhibitors of a caspase-3-dependent pathway and the IC50 values obtained in the yeast assay are in the same order of magnitude of that obtained with the caspase-3 inhibitor tetrapeptidyl chloromethyl ketone, Ac-DEVD-CMK. This observation is consistent with appropriate cell permeability properties displayed by the vinyl sulfone inhibitors, as reflected by logP values ranging from 1.1 to 3.4. Overall, these results suggest that vinyl sulfones containing Asp at P1 should be considered for further optimization as caspase inhibitors and modulators of caspase-3-dependent pathways.
authors: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Paulo M C
authors: PM
authors: Glória
authors: Isabel
authors: I
authors: Coutinho
authors: Lídia M
authors: LM
authors: Gonçalves
authors: Cristina
authors: C
authors: Baptista
authors: Joana
authors: J
authors: Soares
authors: Ana S
authors: AS
authors: Newton
authors: Rui
authors: R
authors: Moreira
authors: Lucília
authors: L
authors: Saraiva
authors: Maria M M
authors: MM
authors: Santos
mesh_terms: D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014753:Vinyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D011994:Recombinant Proteins; D013450:Sulfones; D014753:Vinyl Compounds; D001224:Aspartic Acid; D053148:Caspase 3