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

Abstract

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.