Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies

Abstract

Matrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identification of a sulfide, 4a, bearing an N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1, and MMP-14. Solution complexation studies with Zn were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results.

Ionic liquid-promoted green synthesis of biologically relevant diaryl thioethers

“…The crude was purified by a trituration with n-hexane followed by a flash chromatography (for 5a: 15:1 n-hexane-EtOAc; for 5b: 9:1 n-hexane-EtOAc) affording pure esters 5a (15% yield) or 5b (25% yield) as white solids. The 1 H and 13 C NMR data were in accordance with those reported in the literature (12,13). (For NMR spectra see Supporting info).…”

“…Our starting point was the procedure reported by Matthew et al (25), using 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF 4 ) as solvent. Reactions have been conducted on ethyl ester 4a and benzyl ester 4b ( Table 3, entries 17-20), since better Suzuki crosscoupling results were previously obtained on protected carboxylic acids (12,13).…”

“…Diaryl thioethers are fundamental building blocks for the synthesis of biologically active molecules (10,11). We recently reported (12) the development of novel thioaryl-based matrix metalloproteinase-12 (MMP-12) inhibitors (6c-g, 7c-g, 8-11, Scheme 1) using diaryl thioethers 5a (12) and 5b (13) as key intermediates for the entire synthesis.…”

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…[112] Av ariety of other potentialm etal-binding groups have been evaluated in the Cohen laboratory and by others for their use as zinc chelators in the development of MMP inhibitors. [79,81,82,113]…”

Developments in Carbohydrate-Based Metzincin Inhibitors

“…Recently Rossello’s group reported two series of sugar-based arylsulfonamide carboxylates as MMP-12 inhibitors ( 8–17 and 18–25 , Figure 7 ) [ 76 , 77 ]. Due to the long-time experience of this group into the design and synthesis of MMP-12 inhibitors [ 78 , 79 , 80 , 81 ], a previously published potent and selective arylsulfonamido MMP-12 inhibitor 7 [ 82 ] ( Figure 7 ) was selected as starting compound. The structure of 7 was modified by replacing the aromatic ring on its sulfonamide nitrogen (P2’ position) with a β- N- acetyl- d -glucosamine (GlcNAc) moiety through insertion of a proper spacer.…”