Rational design and development of new prototypes derived of antitumor phospholipids as potential inhibitors of the enzyme CtP: phosphoethanolamine citidililtransferase and antitumor agents in non-small cell lung cancer

Abstract

Due to the relative lack of success of the existent treatments against lung cancers, it is of utmost urgency to develop new, efficient and selective therapies against this disease that is responsible for millions of deaths worldwide. In this regard, the purpose of this proposal is the development of a novel class of drugs candidates, which might offer the possibility of a disease free life to patients. As opposed to the majority of currently chemotherapeutic drugs, antineoplastic phospholipids (AFTs) do not have DNA as a target, but modify the cell membrane turnover, ultimately inducing death by apoptosis, with a high selectivity for tumor cells. The main hypothesis is that the AFT's antitumor effects are due to the inhibition of CTP:phosphocholine cytidylyltransferase enzyme in the phospholipid biosynthetic pathway, known as the Kennedy pathway, which blocks the synthesis of phosphatidylcholine and causes the accumulation of ceramide, commonly associated with apoptosis. Likewise, the inhibition of phosphatidylethanolamine synthesis stops the cell division by preventing the correct progression of cytokinesis, and also induces a topological impairment of the trans-membrane protein domains, mainly those in mitochondria. This, in turn, affects the cellular bioenergetics, eventually triggering death by apoptosis, and impairs lipids signaling, which is directly associated with the regulation of mitogen-activated protein kinase (MAPKs) mediated signaling pathways. Therefore, the inhibition of the phosphatidylethanolamine synthesis constitutes a promising strategy for the identification of novel antitumor compounds, and the CTP:phosphoethanolamine cytidylyltransferase, which is a key enzyme in the Kennedy pathway and uses phophoethanolamine as a substrate, becomes the main potential target, with innovative character, for the development of antitumor drugs. This project aims to establish an interactive and multidisciplinary cycle regarding the development and optimization of novel leads (new chemical entities), acting as CTP:phosphoethanolamine cytidylyltransferase inhibitors as well as antitumor potential agents, integrating the computer-aided drug design (CADD), organic chemistry and experimental evaluation research fields. (AU)