Fighting Cancer through Designed and Natural Products: Discovery of New LDH-A Inhibitors and Route to the Total Synthesis of Rakicidin A

• Main Author: Rupiani, Sebastiano <1988>
• Other Authors: Roberti, Marinella
• Format: Doctoral Thesis
• Language: en
• Published: Alma Mater Studiorum - Università di Bologna 2016
• Subjects: CHIM/08 Chimica farmaceutica
• Online Access: http://amsdottorato.unibo.it/7606/

The present work aimed to synthesizing new biologically active small molecules as innovative antitumor lead candidates and to the total synthesis of a natural compound with selectivity towards cancer hypoxia. In this context, a first project involved the design and synthesis of N-acylhydrazone based inhibitors of lactate dehydrogenase A (LDH-A). The structures of the new molecules where designed by means of virtual screening and synthesized to obtain a library of analogs which were evaluated on the enzyme. Active compounds were also screened on cells of non-Hodgkins lymphoma and one of them proved to be a promising inhibitor, suggesting that the N-acylhydrazone as suitable scaffolds for LDH-A inhibitors. The second project aimed to the synthesis of Galloflavin (GF) analogs and to the study of the compound’s SAR. GF is an LDH-A inhibitor which was previously identified and synthesized by our group. Its poor solubility and stability prevented us from studying its SAR maintaining the core structure. Therefore, the synthesis of three potential classes of structural analogs was devised and carried out. One compound was found to reproduce GF’s behaviour on the enzyme and in cell, therefore being a good starting point for the study. A small library of analogs was synthesized and biological tests are ongoing to acquire in-depth knowledge about the key pharmacophores of this interesting inhibitor. The third project was carried out at Aarhus University in the group of Prof. Thomas Poulsen. The work focused on the total synthesis of Rakicidin A, a macrolide of natural origin which was identified and isolated from soil samples and is known for its interesting properties in selectively inducing cell death in hypoxic environments and being also active on cancer stem cells. The total synthesis involved several steps including key enantioselective reactions to build the 5 stereocenters on the molecule.