| Publication Type |
Journal Article |
| Title |
Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies |
| Authors |
Elisa Nuti Doretta Cuffaro Elisa Bernardini Caterina Camodeca Laura Panelli Sílvia Chaves Lidia Ciccone Livia Tepshi Laura Vera Elisabetta Orlandini Susanna Nencetti Enrico A. Stura M. Amélia Santos Vincent Dive Armando Rossello |
| Groups |
BIOIN |
| Journal |
JOURNAL OF MEDICINAL CHEMISTRY |
| Year |
2018 |
| Month |
May |
| Volume |
61 |
| Number |
10 |
| Pages |
4421-4435 |
| Abstract |
Matrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identification of a sulfide, 4a, bearing an N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1, and MMP-14. Solution complexation studies with Zn2+ were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results. |
| DOI |
http://dx.doi.org/10.1021/acs.jmedchem.8b00096 |
| ISBN |
|
| Publisher |
|
| Book Title |
|
| ISSN |
0022-2623 |
| EISSN |
1520-4804 |
| Conference Name |
|
| Bibtex ID |
ISI:000433403600012 |
| Observations |
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