New matrix metalloproteinase inhibitors based on γ-fluorinated α-aminocarboxylic and α-aminohydroxamic acids.
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.
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany.
Malte
M
Behrends
Klinik für Nuklearmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany.
Stefan
S
Wagner
Klinik für Nuklearmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany.
Klaus
K
Kopka
Klinik für Nuklearmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany.
Otmar
O
Schober
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.
Michael
M
Schäfers
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany.
Sadhana
S
Kumbhar
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.
Mark
M
Waller
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.
Günter
G
Haufe
D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D054879:Halogenation; D006801:Humans; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry
C097658:CGS 27023A; D002264:Carboxylic Acids; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011719:Pyrazines; D013449:Sulfonamides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
Amino hydroxamic acid; CGS 27023A analogues; Fluorine; In vitro assay; Matrix metalloproteinase inhibitors