Purine Derivatives in Cancer Therapy: Structure-Activity Relationships and Recent Advances in Anticancer Drug Development

Abstract

Cancer remains one of the most serious global health challenges, characterized by uncontrolled cellular proliferation resulting from diverse genetic, metabolic, and immunological alterations. Conventional therapies, such as chemotherapy, radiotherapy, and hormonal treatments, though widely used, are often associated with toxicity, resistance, and reduced patient quality of life. Targeted approaches focusing on molecular pathways and metabolic processes are gaining increasing attention, with purine metabolism emerging as a critical area of study. As fundamental building blocks of DNA and RNA, purine nucleotides are indispensable for cell growth and division; aberrations in purine metabolism contribute to tumorigenesis, therapeutic resistance, and metastasis, making purine metabolism a promising therapeutic target. Purine analogues and derivatives have demonstrated considerable potential to disrupt nucleotide synthesis, energy regulation, and signalling pathways in cancer cells. Structure-activity relationship (SAR) studies have revealed that modifications to the purine scaffold-such as pyrazole hybrids, sulfonamide hybrids, halogenated triazoles, and platinum-purine complexes-can enhance potency, selectivity, and binding affinity to molecular targets including EGFR, HER2, Bruton's tyrosine kinase (BTK), and DCLK1. Substituent variations, ring fusions, and halogenation patterns have been shown to influence cytotoxicity, kinase inhibition, and anticancer activity, underscoring the versatility of purine scaffolds in drug design. This review paper explores the pathophysiology of cancer with particular emphasis on the Warburg effect, reviews current therapeutic strategies, and examines purine-based analogues and SAR-guided derivatives as potential anticancer agents. By integrating molecular biology, medicinal chemistry, and SAR analysis, the study highlights the promise of purine-targeted therapies to improve efficacy, reduce toxicity, and overcome resistance. Continued exploration of purine scaffolds may pave the way for next-generation therapeutics with enhanced selectivity and improved therapeutic outcomes.