Towards an MMP-2-activated molecular agent for cancer imaging

Cowell, Simon; Carroll, Laurence; Lavdas, Ioannis; Aboagye, Eric O.; Vilar, Ramón

doi:10.1039/c7dt03108d

Cited by 4 publications

(1 citation statement)

References 23 publications

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“…This has revealed urea derivatives to be the most stable in liver and brain tissues; however, there is no information on cellular toxicity. The major advancement of compound 2 over other currently commercially available inhibitors such as the mentioned hydroxamate-based CGS analogues like compound 1 , therefore, includes the combination of potency, selectivity, and the additional potential for further development of probes capable of distinguishing between MMP-2 versus MMP-9 that could be employed as more specific imaging tools than the currently available MMP tracers. , We therefore developed substituted derivatives of compound 2 .…”

Section: Results and Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Results and Discussionmentioning

confidence: 99%