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

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 (<b>1b</b> and <b>2b</b>) 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, <b>4a</b>, bearing an <i>N</i>-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound <b>4a</b> 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 Zn²⁺ 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

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

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 (<b>1b</b> and <b>2b</b>) 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, <b>4a</b>, bearing an <i>N</i>-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound <b>4a</b> 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 Zn²⁺ 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

Selective Arylsulfonamide Inhibitors of ADAM-17: Hit Optimization and Activity in Ovarian Cancer Cell Models

Activated leukocyte cell adhesion molecule (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form (sALCAM) by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by inhibitors of ADAM-17. In addition, ADAM-17 plays a key role in EGFR signaling and thus may represent a useful target in anticancer therapy. Herein we report our hit optimization effort to identify potent and selective ADAM-17 inhibitors, starting with previously identified inhibitor <b>1</b>. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biological activity of the newly synthesized compounds was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compound <b>21</b>, which showed an IC₅₀ of 1.9 nM on ADAM-17 with greatly increased selectivity. This compound maintained good inhibitory properties on sALCAM shedding in several in vitro assays

<i>N</i>‑<i>O</i>‑Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity

Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9, and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel <i>N</i>-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to the previously discovered compound <b>1</b>. A new series of hydroxamates was designed, synthesized, and tested for their antiangiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9, and MMP-14 inhibitor was identified, compound <b>3</b>, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound <b>3</b> in order to investigate its binding mode to MMP-9 and MMP-14

Tricyclic Sulfonamides Incorporating Benzothiopyrano[4,3‑<i>c</i>]pyrazole and Pyridothiopyrano[4,3‑<i>c</i>]pyrazole Effectively Inhibit α- and β‑Carbonic Anhydrase: X‑ray Crystallography and Solution Investigations on 15 Isoforms

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides <b>3a</b>–<b>e</b> were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides <b>3</b> was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib

Synthesis and Preliminary Evaluation in Tumor Bearing Mice of New ¹⁸F‑Labeled Arylsulfone Matrix Metalloproteinase Inhibitors as Tracers for Positron Emission Tomography

New fluorinated, arylsulfone-based matrix metalloproteinase (MMP) inhibitors containing carboxylate as the zinc binding group were synthesized as radiotracers for positron emission tomography. Inhibitors were characterized by <i>K</i>_i for MMP-2 in the nanomolar range and by a fair selectivity for MMP-2/9/12/13 over MMP-1/3/14. Two of these compounds were obtained in the ¹⁸F-radiolabeled form, with radiochemical purity and yield suitable for preliminary studies in mice xenografted with a human U-87 MG glioblastoma. Target density in xenografts was assessed by Western blot, yielding <i>B</i>_max/<i>K</i>_d = 14. The biodistribution of the tracer was dominated by liver uptake and hepatobiliary clearance. Tumor uptake of ¹⁸F-labeled MMP inhibitors was about 30% that of [¹⁸F]­fluorodeoxyglucose. Accumulation of radioactivity within the tumor periphery colocalized with MMP-2 activity (evaluated by in situ zimography). However, specific tumor uptake accounted for only 18% of total uptake. The aspecific uptake was ascribed to the high binding affinity between the radiotracer and serum albumin