From molecule to medicine: introducing emerging strategies to synthesize potent anticancer purine scaffolds

Cancer remains a major global health concern, necessitating the continuous development of novel anticancer agents with enhanced efficacy and reduced side effects. Purine derivatives are privileged bioactive scaffolds that play a crucial role in drug discovery due to their presence in essential biomolecules such as DNA, RNA, ATP, and coenzymes. This review highlights the synthesis, structure-activity relationships (SARs), and anticancer evaluations of various purine hybrids, including aryl piperazine, triazole-hybrid piperidine/pyrrolidine, and diazenyl-containing purines, from 2020 to 2024. Hybrid molecules incorporating chalcones, thiazoles, thiazolidinones, xanthine, and bis-purine linkers have expanded the therapeutic landscape of purine-based anticancer agents. Comparative analyses of IC₅₀ values reveal that piperazine-containing purine derivatives exhibit potent activity against Huh7, HCT116, and MCF7 cancer cells, while trisubstituted triazole analogs display selective cytotoxicity against A549, IMR-32, HCT-15, and THP-1 cell lines. Moreover, bis-purine derivatives and chalcone-xanthine hybrids exhibit broad-spectrum anticancer potential against A549, HeLa, CFPAC-1, and SW620 cells. Theobromine- and adamantane-based purine scaffolds have emerged as promising anticancer agents, with potent activity against MCF7 and HepG2 cells as well as the VEGFR-2 protein. Comparative SAR studies highlight the role of different heterocyclic substitutions in optimizing anticancer efficacy, offering valuable insights for medicinal chemists in the pursuit of more effective and safer cancer treatments.