Sugar‐Based Arylsulfonamide Carboxylates as Selective and Water‐Soluble Matrix Metalloproteinase‐12 Inhibitors

Abstract

Matrix metalloproteinase-12 (MMP-12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β-N-acetyl-d-glucosamine moiety, were designed and synthesized as MMP-12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP-12 inhibitor with improved water solubility, compound 3 [(R)-2-(N-(2-(3-(2-acetamido-2-deoxy-β-d-glucopyranosyl)thioureido)ethyl)biphenyl-4-ylsulfonamido)-3-methylbutanoic acid], was identified.

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…Furthermore, compound 13 proved to be selective for MMP‐12, with an IC 50 of 40 n m , compared with MMP‐1, ‐2, ‐9, and ‐14 with IC 50 values of 40 000, 320, 5400, and 8900 n m , respectively. The GlcNAc residue, which populates the S2′ site (PDB ID: 5I3M), is exposed to solvent and presents its hydrophilic hydroxy functionalities towards bulk water. The carboxylic acid interacts with the catalytic zinc and with the glutamine in close proximity through the formation of a hydrogen bond.…”

Design and Synthesis of Ionic Liquid‐Based Matrix Metalloproteinase Inhibitors (MMPIs): A Simple Approach to Increase Hydrophilicity and to Develop MMPI‐Coated Gold Nanoparticles

“…Activity was evaluated against MMP‐12 as a target enzyme and against MMP‐2 and MMP‐9 to assess the selectivity of the new compounds. The activity of 1 toward these enzymes has been previously demonstrated . Results are reported in Table as IC 50 values (n m ).…”

“…The synthesis of IL‐based MMP inhibitors 12 a – d and their analogue, thiol 11 , is described in Scheme . The known alkynyl derivative 4 and 1‐azido‐6‐bromohexane 5 were prepared according to published procedures. The azide 5 was conjugated to alkyne 4 by copper‐catalyzed azide–alkyne cycloaddition (CuAAC), according to reported conditions .…”

“…The samples were prepared by deposition of AuNPs suspended and sonicated in ethanol on a 300 mesh carbon‐coated copper grid. Compounds ( R )‐ tert‐ butyl 3‐methyl‐2‐( N ‐(prop‐2‐ynyl)biphenyl‐4‐ylsulfonamido)butanoate ( 4 ) and 1‐azido‐6‐bromohexane ( 5 ) were prepared according to the reported procedures.…”

“…In our ongoing pursuit of MMP‐12 selective inhibitors useful for the treatment of lung and cardiovascular diseases, we recently developed compound 1 (Figure ), a carboxylate‐based sulfonamide endowed with nanomolar affinity for MMP‐12. With the aim of improving the hydrophilicity and bioavailability of this very hydrophobic hit compound without decreasing its affinity for the target, we linked a β‐ N ‐acetyl‐ d ‐glucosamine (GlcNAc) moiety at the P2′ position . Glycoconjugate 2 (Figure ) maintained nanomolar activity for MMP‐12 and good selectivity over MMPs with improved hydrophilicity (water solubility >5 m m and clog P =3.15) with respect to 1 .…”