New in Vivo Compatible Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitors

Abstract

Matrix metalloproteinases (MMPs) are emerging as pivotal fine-tuners of cell function in tissue homeostasis and in various pathologies, in particular inflammation. In vivo monitoring of the activity of specific MMPs, therefore, provides high potential for assessing disease progression and tissue function, and manipulation of MMP activity in tissues and whole organisms may further provide a mode of controlling pathological processes. We describe here the synthesis of novel fluorinated and nonfluorinated analogues of a secondary sulfonamide-based lead structure, compound 2, and test their efficacy as in vivo inhibitors and tracers of the gelatinases, MMP-2 and MMP-9. Using a murine neuroinflammatory model, we show that compound 2 is a highly effective in vivo inhibitor of both MMP-2 and MMP-9 activity with little or no adverse effects even after long-term daily oral administration. A fluorescein-labeled derivative compound 17 shows direct binding to activated gelatinases surrounding inflammatory cuffs in the neuroinflammation model and to pancreatic β-cells in the islets of Langerhans, colocalizing with MMP-2 and MMP-9 activity as detected using in situ zymography techniques. These results demonstrate that compound 2 derivatives have potential as in vivo imaging tools and for future development for specific MMP-2 versus MMP-9 probes. Our chemical modifications mainly target the residues directed toward the S1′ and S2′ pockets and, thereby, provide new information on the structure–activity relationships of this inhibitor type.

Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer

“…MMP-2 and MMP-9, known as gelatinases, can digest type IV collagen and gelatin [ 69 ]. Murname et al showed that MMP-2 protein activity in adenomas with high-grade dysplasia (HGD) was different from adenomas with low-grade dysplasia (LGD).…”

Secretomics reveals gelatinase substrates at the blood-brain barrier that are implicated in astroglial barrier function

“…As an additional control, WT astrocytes were cultured overnight with and without treatment with the chemical inhibitor, (S)-3-methyl-2-{4-[3-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-5-yl]phenylsulfonamido}butanoic acid (MOBSAM), at a concentration that inhibits both MMP-2 and MMP-9 activation ( 18 ). Flow cytometry confirmed that MOBSAM did not adversely affect cell viability (fig.…”

“…Recombinant MMPs were from R&D Systems; p -aminophenylmercuric acetate (APMA; Sigma-Aldrich) was used to activate MMPs; MOBSAM, an N -sulfonylaminoacid derivative, is a dose-dependent inhibitor of MMPs ( 18 ) that was used for the specific inhibition of MMP-9 and/or MMP-2 ( 9 ).…”

Cisplatin combined with capecitabine-induced chemotherapy for local nasopharyngeal carcinoma can improve the quality of life and reduce toxic and side effects

“…The balance of pro-inflammatory cytokine IL-12 plays a key role in shaping the development of anti-tumor or tumor immunity [ 27 ], and the anti-tumor activity of IL-12 can be effectively induced by itself and can be markedly improved by combining with various treatments [ 28 ]. Matrix metalloproteinases (MMPs) are emerging as the key micro-agents of tissue homeostasis and cell function in various pathologies [ 29 ]. However, MMP-2, as one of them, is highly expressed in various pathologies, which interferes with tissue remodeling and inflammatory response.…”