Design, Synthesis and anti-cancer Activity of Acridine Derivatives as mTOR Inhiibitors

Abstract

According to WHO 2015, in India 2.5 million cases were observed per year and 0.3 million deaths occur due to different types of cancers. In women, breast cancer is the most dangerous type of cancer with highest death rate. Despite the development of the several new anticancer agents, there are several limitations which demand the need for the development of more effective and safer anti-cancer drugs. mTOR (mammalian Target of Rapamycin) is highly expressed in many types of cancer like breast, lung, colorectal, renal cell carcinoma etc. After the approval of Everolimus by FDA in 2007, scientist are trying to develop new mTOR inhibitors that could act as anti-cancer agents. So, mTOR is proven to be an attractive target for the treatment of many types of cancer. Here, various computational tools were used for the designing of molecules. In that, two ligand based approaches were carried out i.e. ligand based 3D-QSAR and 2D-HQSAR and ligand based pharmacophore modelling and other techniques like virtual screening, molecular docking, in silico ADMET studies. 39 mTOR inhibitors were selected after extensive literature survey for performing 3D-QSAR studies. Two different alignments were performed. Among whichdistill alignment showed good result as compared to docking based alignments. On the basis of contour maps favourable and unfavourable region were identified.16 diversified structures were taken for the pharmacophore generation. Pharmacophore model was developed using DISCOtech refined GASP module of Sybyl X. The best model was selected which showed 2 hydrophobic, 1 donor atom, 1 acceptor site as essential features. It was further validated through GH and ROC method. Virtual screening which was performed on the generated model which retrieved 57,515 molecules,was further filtered by other filters like counter ions, duplicate structures, bad fragments and Lipinski filtering. Total 21,327 drug like molecules were obtained among which 39 compound showed Qfit value greater than 90%. Molecular docking studies were carried out on designed 2-methoxy-9-substituted acridine derivative using 4DRI as mTORprotein. Best scoring compounds were further synthesized using conventional and microwave methods. Synthesised compounds were further characterized using IR, 1H NMR, 13C NMR and Mass spectrometry.Pharmacological activity of the compounds wereevaluated against MCF-7 cell line which showed that Compound 7d and 7e gave good anti cancer activity. Beside this cytotoxicity studies were also performed, which resulted that compounds were found to be non toxic against VERO cellline.Therefore using various computational tools, 2-methoxy-9-substituted acridine derivatives were designed, synthesized and evaluated for in-vitro studies which can be further utilized for the treatment of anticancer agents.