Synthesis and biological evaluation of delta2-isoxazoline derivatives as DNA methyltransferase 1 (DNMT1) inhibitors

The inactivation of tumor suppressor genes, which often results from epigenetic silencing associated with DNA hypermethylation, plays a pivotal role in the development of most forms of human cancer. To date, there are several reports demonstrating a strictly link between DNA methyltransferase 1 (DNMT1) disregulation and oncogenesis. Nucleoside analogues of cytosine (e.g., 5-azacytidine) effectively inhibit the activity of DNA methyltransferases, but their high cytotoxicity and the low therapeutic index make the development of novel non-nucleoside inhibitors highly desirable. Procaine and procainamide, already used as drugs, exhibit a weak DNA demethylating activity and are “repositionable” as non-nucleoside inhibitors. We recently identified a SAM-competitive D2-isoxazoline constrained analogue of procaine/procainamide as a lead compound for the development of non-nucleoside DNMT inhibitors. Herein we report the synthesis and the biological evaluation of new, longer compounds, achieved by the application of the common “multisubstrate adduct” approach, in order to obtain novel bisubstrate inhibitors of DNMT1 (Figure 1)