Synthesis of 6,8-diaminopurines acid-induced cascade cyclization of 5-aminoimidazole precursors and preliminary anticancer evaluation

• Published in: Organic & biomolecular chemistry 2024-02, Vol.22 (7), p.15-1513
• Main Authors: Senhorães, Nádia R, Silva, Bruna F, Sousa, Raquel, Leite, Bruna P, Gonçalves, Jorge M, Almeida Paz, Filipe A, Pereira-Wilson, Cristina, Dias, Alice M
• Format: Article
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d3ob01985c

Inspired by the pharmacological interest generated by 6-substituted purine roscovitine for cancer treatment, 5-aminoimidazole-4-carboxamidine precursors containing a cyanamide unit were prepared by condensation of 5-amino- N -cyanoimidazole-4-carbimidoyl cyanides with a wide range of primary amines. When these amidine precursors were combined with acids, a fast cascade cyclization occurred at room temperature, affording new 6,8-diaminopurines with the N-3 and N-6 substituents changed relatively to the original positions they occupied in the amidine and imidazole moieties of precursors. The efficacy and wide scope of this method was well demonstrated by an easy and affordable synthesis of 22 6,8-diaminopurines decorated with a wide diversity of substituents at the N-3 and N-6 positions of the purine ring. Preliminary in silico and in vitro assessments of these 22 compounds were carried out and the results showed that 13 of these tested compounds not only exhibited IC 50 values between 1.4 and 7.5 μM against the colorectal cancer cell line HCT116 but also showed better binding energies than known inhibitors in docking studies with different cancer-related target proteins. In addition, good harmonization observed between in silico and in vitro results strengthens and validates this preliminary evaluation, suggesting that these novel entities are good candidates for further studies as new anticancer agents. Novel 6,8-diaminopurines were synthesized using a fast cascade reaction from easily accessible 5-aminoimidazole precursors. Preliminary assessments suggest that the new entities are excellent candidates for further development as anticancer agents.