SYNTHESIS, ACTIVITY, CRYSTAL AND ELECTRONIC PROPERTIES OF ISOMERS OF CHLORO-PYRIDINYLVINYL-1H-INDOLES

Immunotherapy is a promising novel strategy for cancer therapy. It consists of the therapeutic vaccination of cancer patients to stimulate their (natural) immune system against cancer cells. This approach, however, showed limited efficacy in vivo. Cancer cells are actually able to develop enzymatic mechanisms allowing tumours to resist or escape the immune rejection. Among the enzymes involved, the indoleamine 2,3-dioxygenases IDO and TDO represents potential actors[1-3]. These enzymes catalyse the rapid degradation of tryptophan (Trp) through the kynurenine (Kyn) pathway to form quinolinic acid (QA). This results in a local Trp depletion that severely affects the proliferation of T lymphocytes and is thereby profoundly immunosuppressive. This project was funded in part by Télévie (FNRS grant 7.4.543.07) and led in collaboration with the team of Pr Benoit Van Den Eynde (LICR, UCL) and Pr Moreno Galleni (CIP, ULG) aims at developing novel TDO inhibitors using a rational approach. These inhibitors will allow a better understanding of the role of TDO in the phenomenon of immunosuppression, especially in cancerous tumors. The three isomers of chloro-3-(2-pyridin-3-ylvinyl)-1H-indole were synthesized and the crystal structure was determined by X-ray diffraction for two of them. Solubility of the molecules has also been determined experimentally. The molecular electrostatic potential and dipole moments of the three isomers were also calculated by ab initio quantum mechanics (HF/6-311G). This study leads to a better understanding of the structural and electronic characteristics of this chemical series and can potentially help to better understand their inhibitory activity. This process is presented on this poster.