Synthesis, Inhibitory Properties and Crystallographic Studies for the characterization of ligands for soluble MMPs (MMP-8, MMP-9 and MMP-12)

Matrix Metalloproteinases (MMPs) are a family of enzymes that are attracting growing interest as therapeutic targets. The alteration of MMPs expression is related to the manifestation of a series of severe diseases such as autoimmune pathologies, cancer, myocardial infarction, rheumatoid arthritis, Alzheimer's disease. Moreover, MMPs are involved in the control of physiological processes such as ovulation, wound healing and growth. For these reasons, it is important that their activity at both the transcriptional and post-transcriptional level is finely regulated. In order to obtain structural information useful for the design of molecules able to control the signalization pathways, the involved proteins should be crystallized in complex with ligands that induce dimerization. In this PhD Thesis bi-functional drugs have been generated by linking two ligands and the relative crystallizability of complexes with mono-functional and bi-functional ligands have been evaluated. In recent years, several MMPIs have been designed, synthesized and tested in clinical trials. However, most of them, are poorly soluble in water and suffer from a modest oral bioavailability. A limited drug bioavailability requires the administration of large doses of drug to achieve and maintain an effective therapeutic efficacy. This increases the risk of adverse effects due to high doses administered. Water soluble inhibitors are required in many long-term treatments, where a chronic treatment was required, but few MMPIs reported to data shown a good solubility/ bioavailability ratio. Relying on this observation and pre-obtained data, new aryl sulfonamide inhibitors of MMPs conjugated with a sugar portion were synthesized during my PhD work. The compounds were tested in vitro on human recombinant MMPs by fluorometric assay and crystallographic study were conducted.