Towards targeting cancer therapy; design and synthesisof amide based scaffolds

Abstract

Cancer is a generic term for a large group of diseases that can affect any part of the body. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjacent parts of the body and spread to other organs, the latter process is referred to as metastasizing. Metastases are the major cause of death from cancer. Cancer is among the leading causes of death worldwide. In 2012, there were 14 million new cases and 8.2 million cancer-related deaths worldwide.The number of new cancer cases will rise to 22 million within the next two decades.More than 60% of the world’s new cancer cases occur in Africa, Asia, and Central and South America; 70% of the world’s cancer deaths also occur in these regions. Knowledge about the causes of cancer, and interventions to prevent and manage the disease is extensive. Cancer can be reduced and controlled by implementing evidence-based strategies for cancer prevention, early detection of cancer and management of patients with cancer. Many cancers have a high chance of cure if detected early and treated adequately. Adenosine monophosphate-activated protein kinase (AMPK) is a key player in maintaining energy homeostasis in response to metabolic stress. Beyond diabetes and metabolic syndrome, there is a growing interest in the therapeutic exploitation of the AMPK pathway in cancer treatment in light of its unique ability to regulate cancer cell proliferation through the reprogramming of cell metabolism. Previously, a novel thiazolidinedione-based AMPK activator (OSU-53) was identified, which provided a proof-of-concept to highlight the important role of AMPK in regulating oncogenic signaling pathways associated with cell proliferation and epithelial-mesenchymal transition (EMT) in cancer cells. In this study, we used OSU-53 as a scaffold to conduct lead optimization, which generated a library of eighty five derivatives. The design process focused on Identification of key interactions between AMPKα2β1 enzyme allosteric binding site and the reported activator991, modeling studies including docking of OSU-53 into the active site of AMPKα2β1 enzyme and finally rational modification of the lead compound, OSU-53 guided by modeling studies to help establish a clear SAR for this class of compounds. Synthesis of the designed compounds was then accomplished & their structures were confirmed by various spectral and HPLC purity data.