title: Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors.
abstract: As the matrix metalloproteinases (MMPs) can be massively up-regulated in degenerative tissues and degrade the extracellular matrix, these key enzymes are promising targets for the therapy of cancer and other degenerative diseases. Here, we are presenting a series of new non-peptidic hydroxamate-based matrix metalloproteinase inhibitors, MMPIs, incorporating the iminodiacetic (IDA) hydroxamic acid scaffold, as mimics of truncated peptidic MMPIs. A series of alkylaryl and sulfonylaryl groups, on the IDA basic scaffold, was investigated with the aim of improving potency and selectivity against MMPs involved in degenerative diseases. The sulfonamide based IDA derivatives studied (compounds B1-B3) showed to be potent (nM range) against deep S1' pocket MMPs enzymes (i.e., MMP-2).
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Rua Rovisco Pais 1, 1049-001 Lisboa, Portugal. masantos@ist.utl.pt
authors.forename: M Amélia
authors.initials: MA
authors.lastname: Santos
authors.forename: Sérgio M
authors.initials: SM
authors.lastname: Marques
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Paolo
authors.initials: P
authors.lastname: Carelli
authors.forename: Laura
authors.initials: L
authors.lastname: Panelli
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
mesh_terms: D000107:Acetylation; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007097:Imines / Q000737:chemistry*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D007097:Imines; D011480:Protease Inhibitors; D008666:Metalloendopeptidases