New bifunctional metalloproteinase inhibitors: an integrated approach towards biological improvements and cancer therapy.

Abstract

The key role of some matrix metalloproteinases (MMPs) on several pathological processes, including carcinogenesis and tumor growth, makes the development of MMP inhibitors (MMPIs) an attractive approach for cancer therapy. We present herein an integrated approach for the development of a new series of inhibitors of MMP2 and MMP14, two enzymes over-expressed by human ovarian cancer. As a first step, a new series of single model compounds bearing different zinc-binding groups (ZBGs), such as carboxylic, hydroxamic acid, hydrazide and sulfonylhydrazide groups, were studied and revealed reasonably good capacity for the Zn(II) chelation in solution and for the MMP inhibition. Aimed at further reinforcing the biological activity of these MMPIs as anti-cancer agents, a selection of those models was extra-functionalized with benzothiazole (BTA), a group with recognized antitumor activity. Analysis of the results obtained for these bifunctional compounds, in particular the inhibitory activity against MMP2 and MMP14 as well as the anti-proliferative activity on the A2780 ovarian cancer cell line, allowed to understand the activity dependence on the type of ZBG, as well as the relevance of the BTA moiety. Overall, the evidenced BTA-associated activity improvements on enzyme inhibition and cell antiproliferactivity, combined with the hydrolytic stability revealed by the hydrazide group, suggest that these new bifunctional BTA-hydrazide derivatives should be taken in consideration for the development of new generations of MMPIs with anti-cancer activity.

• Authors: Sérgio M Marques, Claudia C Abate, Sílvia Chaves, Fernanda Marques, Isabel Santos, Elisa Nuti, Armando Rossello, M Amélia Santos
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 127 Pg. 188-202 (Oct 2013) ISSN: 1873-3344 [Electronic] United States
• PMID: 23597851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• Ligands
• Matrix Metalloproteinase Inhibitors
• Zinc

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coordination Complexes (chemistry, pharmacology)
• Drug Stability
• Humans
• Inhibitory Concentration 50
• Ligands
• Magnetic Resonance Spectroscopy
• Matrix Metalloproteinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Zinc (chemistry)