Design and development of some heterocycles for treatment of cancer

Abstract

Cancer is a broad term for an assortment of malignancies distinguished by the unchecked division and growth of abnormal cells within the body. These cells may penetrate nearby tissues and migrate to different locations throughout the body via the lymphatic and circulatory systems. Metastasis is the term used to describe the proliferation of cancer cells. Although the chance of developing cancer rises with age, it can occur in practically any tissue or organ and afflict anyone. newline The comprehensive research presented in this thesis underscores the successful application of structure-based drug design strategies for the development of novel anticancer agents targeting Cyclin-Dependent Kinase 8 (CDK8). The initial selection of CDK8 as the therapeutic target was strongly supported by its critical involvement in oncogenic transcriptional regulation and its overexpression in various malignancies, including breast, colon, and melanoma cancers. The refined CDK8 protein structure demonstrated high structural integrity and stability, validated through multiple computational tools, including ProSA, SAVES v6.1, and ERRAT, which confirmed that the model was suitable for downstream docking and simulation studies. newlineMolecular docking of 232 synthesized and designed pyrimidine derivatives against CDK8 (PDB ID: 6T41) revealed promising binding affinities, with several compounds displaying significantly strong interactions. Notably, PB129 and PB71 emerged as lead candidates with excellent binding energies of -12.4 kcal/mol and -12.2 kcal/mol, respectively. These compounds exhibited multiple favorable interactions with key active- site residues such as LEU158, VAL35, HIS106, ALA155, and TYR32, which are critical for potent and specific inhibition. The interaction profiles suggest strong potential for these molecules as CDK8 inhibitors. newlineIn vitro cytotoxicity evaluation using the MTT assay against MCF-7 breast cancer cells provided further evidence of anticancer activity. The standard drug 5-Fluorouracil (5- FU) showed the highest in