Synthesis, SAR, and biological evaluation of alpha-sulfonylphosphonic acids as selective matrix metalloproteinase inhibitors.
Eleven simple alpha-sulfonylphosphonates, new analogues of previously reported alpha-sulfonylaminophosphonates, were prepared and tested as MMP inhibitors. The IC(50) values of most of these compounds are in the nanomolar range against MMP-2, -8, -13, and -14. Compound 11 proved to be the most effective inhibitor of MMP-2 (IC(50) = 60 nM), with interesting selectivity versus the antitarget enzymes MMP-3 and MMP-9. The mode of binding of the new phosphonates in the active site of MMP-2 was studied, and variations in inhibition was explained by means of molecular modeling.
Rubino
Maria Teresa
MT
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Via Orabona 4, 70126 Bari, Italy.
Agamennone
Mariangela
M
Campestre
Cristina
C
Fracchiolla
Giuseppe
G
Laghezza
Antonio
A
Loiodice
Fulvio
F
Nuti
Elisa
E
Rossello
Armando
A
Tortorella
Paolo
P
D003198:Computer Simulation; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D061965:Matrix Metalloproteinase Inhibitors; D063065:Organophosphonates; D013451:Sulfonic Acids; D020782:Matrix Metalloproteinases