Design and synthesis of new potentially inhibitors of PCSK9 and KRAS proteins

Abstract

This thesis shows the research carried out on two specific diseases: familial hypercholesterolemia, which is included within the cardiovascular diseases group, and cancer. These diseases are the major cause of deaths in Spain and worldwide. The study of familial hypercholesterolemia is of great interest, as it is mainly caused by a protein called PCSK9 whose atypical functioning leads to an increase of LDL-C in blood. Thus, the study of new diseases results in the study of new therapeutic targets. Therefore, a thorough investigation on the PCSK9 protein has been conducted by means of molecular modelling analysis. Also, the synthesis of potentially PCSK9 inhibitors new compounds has been performed. The modelling studies have been based on the research of new binding sites and in de novo synthesis of new inhibitors. On the other side, the experimental synthesis of new compounds has been conducted by the preparation of pyrrolo[2,3-d]pyrimidines and finally, by the preparation of a series of compounds analogues of Combretastatin A4 through modification in the two aromatic rings and the fixation of its configuration with the introduction of a cycle. In the case of cancer, the study is based mainly on the research of a key protein in cell proliferation, growth and cell signalling. KRAS protein is either active or mutated in most common cancers, being the main cause of pancreas and colorectal cancer. Research on this target is of high chemical and biological relevance since no drugs have been found to act directly on said target. Molecular modelling studies are performed in order to find the binding site of a reference product whose inhibiting capacity over the protein is known. Furthermore, the synthesis of a series of symmetric pyrazoles with different structural modifications has also been carried out. Additionally, biological WST-8 / CCK8 assay have been performed on some of the synthetized compounds, specifically on two Combretastatin A4 analogues, in an endothelial cell line that allows studying both endothelial dysfunction and cardiovascular diseases. Research on the MAPK signalling pathway has been performed with pyrazoles structure derivatives.