Molecular design and synthesis of certain heterocycles based compounds as potential anti-cancer targeted agents

Abstract

Cancer is considered rapidly propagating disease, in which the cells divide uncontrollably and abnormally, surpassing its usual boundaries and can as well extend to other organ and metastasize. In the meantime, pancreatic cancer is the seventh leading cause of cancer associated death, world widely, and predicted to be the second cause in the developed world by 2030. PI3K family is involved in the normal physiological cell processes such as cell growth, proliferation, adhesion and survival through the production of lipid second messengers, binding to and activating downstream effector proteins. Among that family, the PI3K-α isoform was suggested to be the most frequently altered in human tumors; breast (27%), endometrial (23%), colorectal (14%), urinary tract (17%) and ovarian (8%) cancers. Meanwhile, overexpression of the upstream effectors of PI3K such as K-ras appeared within pancreatic ductal adenocarcinomas that consequently over activates the PI3K pathway, particularly the alpha isoform. Another member of the PI3K family is the PI3K-γ isoform was reported to be over activated by tumor-derived chemo-attractant signals, contributing in subsequent myeloid cell adhesion and invasion into tumors. Therefore, inhibiting such pathway represents an interesting class of rational targets for anticancer agents development. The current study aimed to design novel Furo[2,3-d]pyrimidine based compounds targeting PI3K-α and PI3K-γ isoforms. The design focused on exploring the SAR studies, previously revealed by of the lead compounds possessing anti-cancer activity along with bioisosteric modifications to study the SAR of the newly designed series of compounds. The designed compounds were synthesized and their structures were confirmed by various spectral and micro-analytical methods.