Design and synthesis of novel quinoline-based DNA methyltransferases inhibitors (DNMTi).
DNA methylation occurs at the C5 of cytosine ring, mostly in a CpG dinucleotides context, by transfer of a methyl group from S-adenosyl-L-methionine and is catalyzed by three DNA methyltransferases (DNMTs): DNMT1, DNMT3A, DNMT3B. DNA methylation is a crucial epigenetic modification in modulation of gene expression and it is involved in various physiological processes such as genomic imprinting, chromosome X inactivation, gene silencing, chromosomes stability and repression of transposons. Thus abnormal activity of DNMTs is described in several diseases included cancer. So far, several nucleoside (N) and non-nucleoside (NN) DNMT inhibitors (DNMTi) have been described and studied for their activity against cancer. Two azanucleosides have been approved for the treatment of haematological malignancies but, despite their efficacy, poor bioavailability, chemical instability and severe side-effects have been detected. On the other hand, the non-nucleoside DNMTi available to date, even if less toxic than aza-nucleosides, exhibit low potency and poor specificity for DNMTs, so that none of them is studied for clinical applications. Therefore the discovery of novel, potent and selective non-nucleoside DNMTi still remains an important challenge. SGI-1027 has been described as potent NN-DNMTi able to induce demethylation and re-express Tumor Suppressor Genes (TSGs) silenced by methylation in RKO cancer cells. Recently the group of Prof. A. Mai described MC3343, MC3353, MC2838 and MC2835, a group of DNMTi analogues of SGI-1027, able to inhibit proliferation in several cancer cell lines at µM concentrations. Moreover, tested in peripheral blood mononuclear cells (PBMCs), MC3343 was reported to possess a lower toxicity compared to the SGI-1027.The aim of this project is to further optimize activity, and improve potency and selectivity, of this series of DNMTi.