Design and synthesis of small molecules as tools for drug discovery and chemical biology: identification of new LDH-A inhibitors and development of fluorescent probes to investigate neurogenesis

The present work includes distinct research projects having as common platform the design and synthesis of biologically active small molecules, useful as tools both for drug discovery and chemical biology studies. The main project (Part I) focused on the identification of LDH-A inhibitors as hit candidates in the discovery of new anticancer agents. My work aimed to explore the chemical space around galloflavin (GF) by synthesizing a small library of analogs to perform structure-activity relationships (SAR) studies. GF, LDH-A inhibitor previously identified and synthesized by our group, was not investigated in terms of SAR because of its poor chemical tractability. In the present work, natural urolithin M6 (UM6) has been selected as simplified analog of GF. It is endowed with improved physicochemical properties and showed to reproduce GF’s biological behaviour. An efficient synthetic strategy has been developed to obtain UM6, which synthesis was not previously reported. This route gave an easy access to a series of structural analogs for SAR investigation. The second project (Part II), carried out at Oxford University under the supervision of Professor Angela Russell, aimed to use a chemical biology approach to develop a proneurogenic small molecule recently identified by the group (OX02672), into a fluorescent probe to assess its molecular interactions and localization in neural stem cells (NSCs). My work focused on the design and synthesis of alkyne-tagged derivatives of OX02672 for subsequent development into probes by “click” conjugation with azide-containing fluorophores. The third part includes a side-project (Part III), carried out in collaboration with group of Professor Maria Laura Bolognesi. It focused on the design and synthesis of multi-target-directed ligands (MTDLs) useful as potential hit candidates in the search for new drugs against Alzheimer’s disease (AD). Tacrine-resveratrol hybrid compounds have been designed and synthesized by using a fusing strategy.