43. Synthesis, Antiproliferative Activity, and Molecular Modelling of New DNA Intercalating Pyridophenoxazinone Carboxamides

Clinical studies have shown that multimodal therapy, a combination of anticancer treatments acting simultaneously on different biological targets is able to inhibit the proliferation of tumor cells present in different phases of the cell cycle. This new therapeutic approach improves the patient's survival and decreases the drug resistance. To obtain new antiproliferative compounds able to act through multimodal mechanisms on the cancerous cells, including DNA intercalation and topoisomerase inhibition, derivatives of pyridophenoxazinone carboxylic acids the carboxamides 1a-d and 2a-d, holding at C-9 and C-10 positions an aminoacidic chain, were designed by molecular modelling calculation, synthesized and evaluated for their inhibitory effect on a panel of solid and liquid tumor cell lines and found active at submicromolar concentration. Compound 2a was the most active, particularly on solid tumors. From preliminary results the derivatives 1-2, designed to intercalate the DNA double helix at the guanine/cytosine sequences form a stable complex where the aminoacidic chain protrudes into the major grove to interact topoisomerases enzymes. The DNA undergoes a multimodal simultaneous attack and its synthesis results to be inhibited by block of topoisomerase and polymerase action.