Attractive approaches in anticancer therapy: a challenge posed by natural products

Part A. Total synthesis, biological evaluation and SAR studies of Smo and Gli antagonists Hedgehog (Hh) signaling pathway is essential for tissue homeostasis, development and stemness. Since Hh pathway possesses a critical role in cancer initiation, proliferation, metastasis, chemoresistance and in the survival of CSCs, its constituents represent attractive druggable targets for anticancer therapy. With the aim to inhibit the pathway at the upstream receptor Smoothened (Smo) or the downstream effector Gli1, small molecules as emerged as promising anticancer agents. The natural isoflavone Glabrescione B (GlaB) emerged as the first small molecule binding to Gli1 zinc-finger and debilitating Gli1 activity by interfering with its interaction with DNA. Here, taking advantage by the versatile isoflavone scaffold, we have designed, synthesized and tested new Hh inhibitors. The rational introduction of defined substitutions on the isoflavone’s ring B, led us to identify molecules targeting preferentially Gli1 or Smo. Thanks to a multidisciplinary approach, combining chemical, biological and molecular docking fields, it was possible obtain new insights into the mechanism of action of these molecules. The co-administration of two different isoflavones behaving as Smo and Gli antagonists in primary mudulloblastoma (MB) cells, emphasized the synergistic effects of these agents, hence paving the way to additional and innovative strategies for the pharmacological inhibition of Hh signaling. Part B. Toward the total synthesis of madangamine B Marine natural products show increasing interest in biological, ecological, pharmacological and chemical fields1-3. Since their secondary metabolites possess structures not identified in terrestrial organisms, endowed by significant biological activities, they are intriguing candidates as lead compound for drug discovery1-4. Madangamines (A-F), a class of diazapentacyclic alkaloids, were discovered (A-E) by Andersen and co-workers since 1992 from a sponge of the genus Haposclerida, family Petrosiidae, collected off Madang, in Papua New Guinea. The same authors reported in 1994 the isolation of madangamine A, found in the marine sponge Xestospongia ingens, and few years later they described four new related alkaloids, labelled madangamines B-E. It had to wait until 2005 to reach the isolation of madangamine F from Pachychalina alcaloidifera, accomplished by Berlinck and co-workers and reported in 2007. Pure madangamines A-C and F were isolated as optically active compounds3; madangamines D and E were isolated as inseparable mixture2. Until 2014 the absolute configuration of madangamines was only presumed, and it has been hypothesized on the basis of an ingenamine, which is considered a putative precursor of madangamines. The assignment of the absolute configuration of (+)-madangamine D, is based on its first total synthesis by Amat and co-workers11. As had been described for the natural products, synthetic madangamine D has been found dextrorotatory, having unambiguous 2S, 5S, 9R, 12R absolute configuration of this alkaloid family. Madangamines A and F exhibited, in vitro, M IC50 values against a multitude of cancer cell lines, both human and murine’s ones. Thanks to the collaboration with PharmaMar Company it was been possible test the activity of madangamine D, that showed in vitro significant cytotoxic activity against pancreas (GI50 7.4 μg/mL) and colon cancers (GI50 4.4 μg/mL).