New matrix metalloproteinase inhibitors based on γ-fluorinated α-aminocarboxylic and α-aminohydroxamic acids

Malte Behrends; Stefan Wagner; Klaus Kopka; Otmar Schober; Michael Schäfers; Sadhana Kumbhar; Mark Waller; Günter Haufe

doi:10.1016/j.bmc.2015.03.078

New matrix metalloproteinase inhibitors based on γ-fluorinated α-aminocarboxylic and α-aminohydroxamic acids

Bioorg Med Chem. 2015 Jul 1;23(13):3809-18. doi: 10.1016/j.bmc.2015.03.078. Epub 2015 Apr 6.

Authors

Malte Behrends¹, Stefan Wagner², Klaus Kopka², Otmar Schober², Michael Schäfers³, Sadhana Kumbhar¹, Mark Waller⁴, Günter Haufe⁵

Affiliations

¹ Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany.
² Klinik für Nuklearmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany.
³ Klinik für Nuklearmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany; European Institute for Molecular Imaging, Westfälische Wilhelms-Universität Münster, Waldeyerstraße 15, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany.
⁴ Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany.
⁵ Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany. Electronic address: haufe@uni-muenster.de.

PMID: 25921268
DOI: 10.1016/j.bmc.2015.03.078

Abstract

Matrix metalloproteinases (MMPs) are involved in a number of physiological as well as pathological processes such as atherosclerosis and tumorigenesis, where an up-regulation of MMPs is predominant. Fluorinated analogues of the hydroxamate-based non-peptidic broad-spectrum MMP inhibitor (MMPI) CGS 27023A were synthesized and inhibition potencies for MMP-2 and MMP-9 in the nanomolar range were measured using fluorimetric in vitro assays. The inhibition potencies of the herein reported fluorinated MMPIs were comparable or even superior in some cases to their non-fluorinated analogues. In contrast to the lead structure, both enantiomers of fluorinated MMPs were almost equally potent. Modelling studies suggest that the core α-amino hydroxamic acid residues appear to influence the relative potencies via specific inhibitor-peptidase interactions, including short fluorine-hydrogen contacts, within the enzyme's pockets. The binding of the essential hydroxamate group to the zinc ion is rather unaffected by the rest of the molecule. In contrast, the corresponding α-aminocarboxylic acid derivatives are 10(3) times less potent or were even inactive.

Keywords: Amino hydroxamic acid; CGS 27023A analogues; Fluorine; In vitro assay; Matrix metalloproteinase inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Carboxylic Acids / chemical synthesis*
Carboxylic Acids / chemistry
Halogenation
Humans
Hydrogen Bonding
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / chemistry
Matrix Metalloproteinase 2 / chemistry*
Matrix Metalloproteinase 9 / chemistry*
Matrix Metalloproteinase Inhibitors / chemical synthesis*
Matrix Metalloproteinase Inhibitors / chemistry
Models, Molecular
Molecular Structure
Protein Binding
Protein Conformation
Pyrazines / chemical synthesis*
Pyrazines / chemistry
Sulfonamides / chemical synthesis
Sulfonamides / chemistry

Substances

CGS 27023A
Carboxylic Acids
Hydroxamic Acids
Matrix Metalloproteinase Inhibitors
Pyrazines
Sulfonamides
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9