Design and synthesis of heterocyclic compounds potentially antitumor by enzymatic inhibition

Resumen

This doctoral thesis is focused on the investigation and development of new compounds directed to different cancer and tropical diseases targets. Drug resistance, as well in cancer as in tropical diseases, is a hurdle which in the latest years it is driving the scientific community to investigate in new diagnostic techniques, to improve in genomic sequencing, as well as to develop new treatments through the synthesis of new small molecules, for example. The physiologic framework, that drives to resistance, is complex and for this reason, personalized treatments is an increasing concept and needed in order to improve the prognostic of the patients. Therefore, we are looking for compounds acting on multiple targets, with selectivity to diminish the adverse effects and increase the treatments efficacy. Two different synthetic routes have been carried out: the first, taking as a main nucleus the 1-spiro[benzodioxole-2,4’-piperidine], from which a wide variety of derivatives was obtained. The second route is the preparation of pyrrolo[2,3-b]pyrazine derivatives, then obtaining a purine and pyrimidine analogues. All compounds were developed through classical chemistry reactions, purified by means of separation techniques (chromatography), and their structural elucidation was accomplished for every one of them. In order to test the compounds in different therapeutical targets, Eli Lilly laboratories have undertaken a high throughput screening in several targets related with cancer, tropical diseases, diabetes, amongst others. In addition, quantitative biological assays have been made to characterize aGPCRs, the receptors involved in different disorders such as cancer or cardiovascular diseases, providing information needed for their crystallization and their study as new targets.