Carbamoylphosphonate-based matrix metalloproteinase inhibitor metal complexes

Solution studies and stability constants. Towards a zinc-selective binding group

E. Farkas, Yiffat Katz, Sudhakar Bhusare, Reuven Reich, Gerd Volker Röschenthaler, Martin Königsmann, Eli Breuer

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Overactive matrix metalloproteinases (MMPs) are associated with a variety of disease states. Therefore, their inhibition is a highly desirable goal. Yet, more than a decade of worldwide activity has not produced even one clinically useful inhibitor. Because of the crucial role of zinc in the activity of the enzyme, the design of inhibitors is usually based upon a so-called zinc binding group (ZBG). Yet, many of the hitherto synthesized potent inhibitors failed clinically, presumably because they bind stronger to metals other than zinc. We have developed in vivo potent inhibitors based on the carbamoylphosphonic group as a putative ZBG. In this paper we report stability constants for Ca(II), Mg(II), Zn(II) and Cu(II) complexes of two potent, in vivo active, MMP inhibitors, cyclopentylcarbamoylphosphonic acid (1) and 2-(N,N-dimethylamino)ethylcarbamoylphosphonic acid (2). Precipitation prevented the determination of stability constants for iron(III) complexes of 1 and 2. For comparison with carbamoylphosphonates 1 and 2, we synthesized 2-cyclohexyl-1,1-difluoroethylphosphonic acid (3), which does not inhibit MMP, and determined the stability constants of its complexes with Mg(II), Ca(II) and Zn(II). Comparison with the values obtained from the complexes of 1 and 2 with those from 3 indicates participation of the C = O group in the metal binding of the former compounds. The complex stability orders for both 1 and 2 are Ca(II) 〈 Mg(II) 〈 Zn(II) 〈 - Cu(II). In addition, the results indicate that at pH > 8 the dimethylamino group of compound 2 can also participate in the binding of the transition metals Cu and Zn. On the other hand, the amino group in carbamoylphosphonic acid 2 lowers the stability of the complexes with metals favoring oxygen ligands (Ca, Mg and Fe) and increases the selectivity towards Zn. These results are helpful for rationalizing the results observed on our MMP inhibitors hitherto examined, and are expected to be useful for the design of new selective inhibitors.

Original languageEnglish
Pages (from-to)307-315
Number of pages9
JournalJournal of Biological Inorganic Chemistry
Volume9
Issue number3
DOIs
Publication statusPublished - Apr 2004

Fingerprint

Matrix Metalloproteinase Inhibitors
Coordination Complexes
Zinc
Acids
Metals
Matrix Metalloproteinases
Enzyme Inhibitors
Iron
Transition metals
Oxygen
Ligands

Keywords

  • Carbamoylphosphonic acids
  • Matrix metalloproteinase inhibitors
  • Metal complexes
  • Zinc binding groups

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Carbamoylphosphonate-based matrix metalloproteinase inhibitor metal complexes : Solution studies and stability constants. Towards a zinc-selective binding group. / Farkas, E.; Katz, Yiffat; Bhusare, Sudhakar; Reich, Reuven; Röschenthaler, Gerd Volker; Königsmann, Martin; Breuer, Eli.

In: Journal of Biological Inorganic Chemistry, Vol. 9, No. 3, 04.2004, p. 307-315.

Research output: Contribution to journalArticle

Farkas, E. ; Katz, Yiffat ; Bhusare, Sudhakar ; Reich, Reuven ; Röschenthaler, Gerd Volker ; Königsmann, Martin ; Breuer, Eli. / Carbamoylphosphonate-based matrix metalloproteinase inhibitor metal complexes : Solution studies and stability constants. Towards a zinc-selective binding group. In: Journal of Biological Inorganic Chemistry. 2004 ; Vol. 9, No. 3. pp. 307-315.
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N2 - Overactive matrix metalloproteinases (MMPs) are associated with a variety of disease states. Therefore, their inhibition is a highly desirable goal. Yet, more than a decade of worldwide activity has not produced even one clinically useful inhibitor. Because of the crucial role of zinc in the activity of the enzyme, the design of inhibitors is usually based upon a so-called zinc binding group (ZBG). Yet, many of the hitherto synthesized potent inhibitors failed clinically, presumably because they bind stronger to metals other than zinc. We have developed in vivo potent inhibitors based on the carbamoylphosphonic group as a putative ZBG. In this paper we report stability constants for Ca(II), Mg(II), Zn(II) and Cu(II) complexes of two potent, in vivo active, MMP inhibitors, cyclopentylcarbamoylphosphonic acid (1) and 2-(N,N-dimethylamino)ethylcarbamoylphosphonic acid (2). Precipitation prevented the determination of stability constants for iron(III) complexes of 1 and 2. For comparison with carbamoylphosphonates 1 and 2, we synthesized 2-cyclohexyl-1,1-difluoroethylphosphonic acid (3), which does not inhibit MMP, and determined the stability constants of its complexes with Mg(II), Ca(II) and Zn(II). Comparison with the values obtained from the complexes of 1 and 2 with those from 3 indicates participation of the C = O group in the metal binding of the former compounds. The complex stability orders for both 1 and 2 are Ca(II) 〈 Mg(II) 〈 Zn(II) 〈 - Cu(II). In addition, the results indicate that at pH > 8 the dimethylamino group of compound 2 can also participate in the binding of the transition metals Cu and Zn. On the other hand, the amino group in carbamoylphosphonic acid 2 lowers the stability of the complexes with metals favoring oxygen ligands (Ca, Mg and Fe) and increases the selectivity towards Zn. These results are helpful for rationalizing the results observed on our MMP inhibitors hitherto examined, and are expected to be useful for the design of new selective inhibitors.

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