Design and Synthesis of Novel mTOR Inhibitors as Anticancer Agents

Abstract

xiii newlineAbstract newlineprotection and deprotection chemistry were utilized for the selective nitration at the 6th position of newlinethe THQ which gave N-substituted 6-nitrotetrahydorquinoline. Further reduction was carried out newlinewith the aid of zinc/ammonium chloride resulted in the N-substituted 6-aminotetrahydorquinoline. newlineFinal desired compounds were synthesized by the derivatization of the amino group presented at newlinethe 6th position of N-substituted THQ derivatives. All these synthesized compounds were newlinecharacterized by 1H, 13C NMR, Mass analysis, and FTIR while the purity was checked with the newlineHPLC. All these compounds were screened for the antiproliferative activity against the panel of newlinecancerous cell line along with cellular mTOR enzyme assay where 6 compounds were found to be newlinepotent which further taken for the specialized in-vitro biological evaluation viz. colony forming newlineassay, flow cytometric analysis, gene expression study and western blot analysis. Based upon all newlinethese study compounds HB-UC-1 (145d) and HB-UC-5 (145h) were found to best against the lung newlinecancer and mTOR. These two compounds were further taken for in-vivo biological evaluation. newlineInitially, the effect of compounds HB-UC-1 (145d) and HB-UC-5 (145h) on the lifespan of cancerbearing animals were evaluated up to 30 days where these compounds gave a promising newlineoutcome. Further, these compounds were taken for the testing in the bezo[a]pyrene induced lung newlineThe present research work was started with the detailed literature review on cancer. It was newlineobserved that lung cancer is one of the dangerous cancer among all the other type of cancer. Many newlinegenes get mutated in lung cancer but the involvement of EGFR, KRAS, PTEN and PIK3CA are newlinemore common. Unavailability of drugs or resistance to the available drugs is the major problem in newlinethe treatment of lung cancer. In the present research, mTOR was selected as an alternative target newlinefor the treatment of lung cancer which involves the PI3K/AKT/mTOR pathway. For the newlineidentification of the core scaffold, pharmacophore modelling was ca