Arsenicin A from the marine sponge Echinochalina bargibanti as a drug lead: Synthesis and antitumor evaluation of related arsenicals

Arsenic is a paradoxical element, because it is a highly toxic and a notorious carcinogen, but it can be a charming medicine. Significant examples of arsenic based drugs are Salvarsan, used as a remedy for syphilis and arsenic trioxide (ATO), FDA approved in 2000 for the treatment of acute promyelocytic leukemia. Arsenicin A (C3H6As4O3) is the first polyarsenic compound ever found in Nature, characterized by an adamantane structure. It was reported in 2006, isolated in our laboratory from the New Caledonian sponge Echinochalina bargibanti. Based on the knowledge acquired so far, the potential of arsenicin A as a promising lead in drug development warranted structure-activity relationship studies on synthetic analogues. Therefore to broaden the molecular diversity, a series of isomeric methylene homologues, including the natural product itself, has been recently obtained by an efficient microwave-assisted synthesis, starting from arsenic (III) oxide. Due to the poor diagnostic value of the NMR analysis in the structural elucidation of these molecules, mass spectrometry and comparison of experimental infrared (IR)-spectra with density functional theory (DFT) simulated ones were decisive. From in vitro screening carried out on the NCI full panel of human cancer cell lines, each tested arsenical resulted in being more active than ATO. In particular the most lipophilic molecule in the series exhibited the best growth inhibition of both leukemia and solid tumor cell lines. These results offer promising perspectives in the development of new more potent and selective arsenical drugs against solid tumors. The most recent achievements will be also presented.