Protease inhibitors: synthesis of bacterial collagenase and matrix metalloproteinase inhibitors incorporating arylsulfonylureido and 5-dibenzo-suberenyl/suberyl moieties.
Novel matrix metalloproteinase (MMP)/bacterial collagenase inhibitors are reported, considering the sulfonylated amino acid hydroxamates as lead molecules. A series of compounds was prepared by reaction of arylsulfonyl isocyanates with N-(5H-dibenzo[a,d]cyclohepten-5-yl)- and N-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl) methyl glycocolate, respectively, followed by the conversion of the COOMe to the carboxylate/hydroxamate moieties. The corresponding derivatives with methylene and ethylene spacers between the polycyclic moiety and the amino acid functionality were also obtained by related synthetic strategies. These new compounds were assayed as inhibitors of MMP-1, MMP-2, MMP-8 and MMP-9, and of the collagenase isolated from Clostridium histolyticum (ChC). Some of the new derivatives reported here proved to be powerful inhibitors of the four MMPs mentioned above and of ChC, with activities in the low nanomolar range for some of the target enzymes, depending on the substitution pattern at the sulfonylureido moiety and on the length of the spacer through which the dibenzosuberenyl/suberyl group is connected with the rest of the molecule. Several of these inhibitors also showed selectivity for the deep pocket enzymes (MMP-2, MMP-8 and MMP-9) over the shallow pocket ones MMP-1 and ChC.
Ilies
Monica
M
Università degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Via della Lastruccia 3, Rm 188, Polo Scientifico, 50019-Sesto Fiorentino, Firenze, Italy.
Banciu
Mircea D
MD
Scozzafava
Andrea
A
Ilies
Marc A
MA
Caproiu
Miron T
MT
Supuran
Claudiu T
CT
D001190:Arylsulfonates / Q000737:chemistry; D002210:Caprylates; D003998:Dicarboxylic Acids / Q000737:chemistry; D015195:Drug Design; D004355:Drug Stability; D006000:Glycocholic Acid / Q000737:chemistry; D017953:Isocyanates / Q000737:chemistry; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001190:Arylsulfonates; D002210:Caprylates; D003998:Dicarboxylic Acids; D017953:Isocyanates; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; C005738:suberic acid; D020782:Matrix Metalloproteinases; D003012:Microbial Collagenase; D006000:Glycocholic Acid