Influence of N-arylsulfonamido d-valine N-substituents on the selectivity and potency of matrix metalloproteinase inhibitors

Christian Paul Konken; Bernd Beutel; Benjamin Schinor; Jian Song; Hanna Gerwien; Eva Korpos; Miriam Burmeister; Burkhard Riemann; Michael Schäfers; Lydia Sorokin; Günter Haufe

doi:10.1016/j.bmc.2023.117350

Influence of N-arylsulfonamido d-valine N-substituents on the selectivity and potency of matrix metalloproteinase inhibitors

Bioorg Med Chem. 2023 Jul 15:90:117350. doi: 10.1016/j.bmc.2023.117350. Epub 2023 May 31.

Authors

Affiliations

¹ Organic Chemistry Institute, University of Münster, Corrensstraße 40, 48149 Münster, Germany; Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
² Organic Chemistry Institute, University of Münster, Corrensstraße 40, 48149 Münster, Germany.
³ Cells-in-Motion Interfaculty Centre (CiMIC), University of Münster, 48149 Münster, Germany; Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Waldeyerstraße 15, 48149 Münster, Germany.
⁴ Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
⁵ Cells-in-Motion Interfaculty Centre (CiMIC), University of Münster, 48149 Münster, Germany; Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany; European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, 48149 Münster, Germany.
⁶ Organic Chemistry Institute, University of Münster, Corrensstraße 40, 48149 Münster, Germany; Cells-in-Motion Interfaculty Centre (CiMIC), University of Münster, 48149 Münster, Germany. Electronic address: haufe@uni-muenster.de.

PMID: 37270903
DOI: 10.1016/j.bmc.2023.117350

Abstract

To develop matrix metalloproteinase inhibitors (MMPIs) for both therapy and medicinal imaging by fluorescence-based techniques or positron-emission tomography (PET), a small library of eighteen N-substituted N-arylsulfonamido d-valines were synthesized and their potency to inhibit two gelatinases (MMP-2, and MMP-9), two collagenases (MMP-8, and MMP-13) and macrophage elastase (MMP-12) was determined in a Structure-Activity-Relation study with ({4-[3-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-5-yl]phenyl}sulfonyl)-d-valine (1) as a lead. All compounds were shown to be more potent MMP-2/-9 inhibitors (nanomolar range) compared to other tested MMPs. This is a remarkable result considering that a carboxylic acid group is the zinc binding moiety. The compound with a terminal fluoropropyltriazole group at the furan ring (P1' substituent) was only four times less potent in inhibiting MMP-2 activity than the lead compound 1, making this compound a promising probe for PET application (after using a prosthetic group approach to introduce fluorine-18). Compounds with a TEG spacer and a terminal azide or even a fluorescein moiety at the sulfonylamide N atom (P2' substituent) were almost as active as the lead structure 1, making the latter derivative a suitable fluorescence imaging tool.

Keywords: Fluorescence imaging; Matrix metalloproteinase inhibitors; N-arylsulfonamido d-valines; Organic synthesis; Structure-Activity-Relations.

Publication types

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

MeSH terms

Carboxylic Acids
Matrix Metalloproteinase 2*
Matrix Metalloproteinase Inhibitors* / pharmacology
Structure-Activity Relationship
Valine

Substances

Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 2
Valine
Carboxylic Acids