Synthesis and Evaluation of Analogues of N-Phthaloyl-L-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1.
Résumé
: DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-Phthaloyl-L-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogs were synthesized to understand its interaction with DNMT. The indole, carboxylate and phthalimide moieties were modified. Homologated and conformationally constrained analogs were prepared. The latter were synthesized from prolino-homotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.