Type

Journal Article

Authors

John Gilmer
Carlos Medina Martin
Jun Wang
Marek Radomski

Subjects

Biochemistry

Topics
barbiturates inhibitors cancer cell mmp 9 matrix metalloproteinases cell migration biochemistry tetradecanoylphorbol acetate

N-subsituted homopiperazine barbiturates as gelatinase inhibitors (2011)

Abstract Matrix metalloproteinases are implicated in a wide range of pathophysiological processes and potent selective inhibitors for these enzymes continue to be eagerly sought. 5,5-Disubstituted barbiturates hold promise as inhibitor types being stable in vivo and relatively selective for the gelatinases (MMP-2 and MMP-9). In this paper we describe the synthesis of 5-piperazine and -homopiperazine substituted barbiturates. The activity of these compounds as gelatinase inhibitors was evaluated using supernatants from 12-O-tetradecanoylphorbol-13-acetate (PMA) - stimulated HT-1080 cells as well as using recombinant human MMPs. N-acyl homopiperazine compounds were found to be potent inhibitors of the gelatinases (range in nM) and generally more potent than the corresponding piperazine analogs. The panel of N-acyl homopiperazines was enlarged in order to exploit differences between the gelatinases at the S2? site in order to design MMP-2- or MMP-9-selective inhibitors. Compounds in this group exhibited single digit nano-molar potency and some selectivity between the two enzymes. Representative potent compounds were effective inhibitors of cancer cell migration.
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Full list of authors on original publication

John Gilmer, Carlos Medina Martin, Jun Wang, Marek Radomski

Experts in our system

1
John Gilmer
Trinity College Dublin
Total Publications: 28
 
2
Carlos Medina Martin
Trinity College Dublin
Total Publications: 28
 
3
Jun Wang
Trinity College Dublin
Total Publications: 37
 
4
Marek W Radomski
Trinity College Dublin
Total Publications: 44