Design, Synthesis and Anticancer Screening of Novel Pyrimimidine Derivatives

Abstract

Cancer is one of the death causing disease all around the world. The Anaplastic Lymphoma Kinase (ALK) is receptor tyrosine kinase (RTK) belonging to insulin receptor subfamily is one of the target for many type of cancers. The oncogenic activation of ALK was observed from very rare cancer to most prevalent non-small cell lung cancer (NSCLC) and ALK mutation were responsible for the disease state. More than two dozens of ALKfusion proteins were reported. This mutation had generated the failure in current therapy by the resistance mechanism. So, there is a need for a potential candidate which can effectively act on target as well as overcome the problem of resistance. In present study, computer aided drug design was done which includes 3D-QSAR, Pharmacophore and Virtual screening. In 3D-QSAR, the classical CoMFA and CoMSIA methods were implemented for generation off models and PLS analysis was used for validation of models. Pharmacophore model was generated using GALHAD module of Sybyl-X software. The validation of pharmacophore model was performed by GH scoring and ROC Curve method. Further, Virtual screening was done on the best Pharmacophore model using NCI database which after application of different filters lead to the hits having different scaffold. The designing of molecules were done based molecular modelling studies. The designed molecules were subjected for the docking as well as molecular dynamics and simulations studies. The top scoring molecules were synthesized by liquid phase synthesis and anti-cancer screening was performed on six molecules out of which three molecules showed anticancer activity.