Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors.
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).
Santos
M Amélia
MA
Centro de Química Estrutural, Instituto Superior Técnico, Rua Rovisco Pais 1, 1049-001 Lisboa, Portugal. masantos@ist.utl.pt
Marques
Sérgio M
SM
Tuccinardi
Tiziano
T
Carelli
Paolo
P
Panelli
Laura
L
Rossello
Armando
A
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
D006877:Hydroxamic Acids; D007097:Imines; D011480:Protease Inhibitors; D008666:Metalloendopeptidases