Design, Synthesis and Development of Hit Compounds able to Modulate some Bio-Pharmacological Activities of Metalloenzymes Involved in Degenerative Diseases

Matrix Metalloproteinases (MMPs) are a family of enzymes that are attracting growing interest as therapeutic targets. They are proteases whose fundamental role has been recognised in the degradation of the Extracellular Matrix (ECM) components. Their expression is finely regulated at many levels (transcription, activation, inhibition) while unregulated profiles have been found in many pathological conditions such as cancer, arthritis, atherosclerosis, and inflammatory diseases. Since the use of endogenous inhibitors is not easy to accomplish, the design and synthesis of new small molecules that could allow the regulation of these proteins is an avanguard in nowadays research of new anticancer drugs, as well as for other therapies. The research project of my PhD thesis focused mainly on four topics:  Synthesis and biological evaluation of arylsulfones and thioaryl derivatives bearing alternative zinc-binding groups as MMP-12 inhibitors  Synthesis and biological evaluation of new sugar-based arylsulfonamide carboxylates as MMP- 12 inhibitors with improved water solubility  Synthesis and biological evaluation of bifunctional ligands of MT1-MMP  Biological evaluation of selective ADAM-10 inhibitors able to inhibit DDR1 and DDR2 shedding