Abstract
The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.
Highlights
Introduction published maps and institutional affilCancer has been the leading cause of death in recent years
2-Aminopyrimidine-based derivatives exhibit a broad spectrum of activities, the synthesis of these compounds has attracted attention for many decades, and the development of new methods for the synthesis of these compounds continues to be of great interest
Numerous studies have indicated the critical role of aurora kinases (AURK) and polo-like kinases (PLK) in cancer cell proliferation
Summary
2-Aminopyrimidine-based derivatives exhibit a broad spectrum of activities, the synthesis of these compounds has attracted attention for many decades, and the development of new methods for the synthesis of these compounds continues to be of great interest. The synthesis of substituted pyrimidines involves two general methodologies. One method involves condensation of moieties with required substituents to get the heterocycle. Another method involves replacement of the substituent at position 2 of the pyrimidine ring with an amino group. The second method is less efficient and gives target products in low yields, in the reactions with arylamines, that require a large excess of nucleophiles [33]
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