ABSTRACT
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 IC50 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.
Subject(s)
Antineoplastic Agents , Molecular Structure , Structure-Activity Relationship , Antineoplastic Agents/chemistry , Cyclization , Imidazoles/pharmacology , Purines/pharmacology , Amidines/pharmacology , Cell Line, Tumor , Molecular Docking Simulation , Drug Screening Assays, Antitumor , Cell ProliferationABSTRACT
Avaliamos 39 crianças, entre 5 e 16 anos, todas com índice de massa corporal (IMC) acima do percentil 95 para sexo e idade, tentando estabelecer relações entre resistência insulínica, idade, sexo, triglicérides, colesterol,acantose nigricans e história familiar de DM tipo 2. Ainda dividimos a amostra em 2 subgrupos, 5-10 anos e 10-16 anos. Foi realizado o teste de tolerância à glicose oral (TTGO) e calculado o HOMA de todos os indivíduos. Das crianças avaliadas 5,1% (meninas do grupo 10-16 anos) apresentaram DM tipo 2, 15,4% intolerância à glicose e 90,8% resistência insulínica. O grupo 10-16 anos apresentou maiores valores de colesterol e triglicérides. As meninas do grupo 10-16 anos apresentaram maiores valores de HOMA que os meninos, enquanto no grupo 5-10 os meninos apresentaram-se mais insulino-resistentes que as meninas. Concluímos que a maioria de nossas crianças obesas apresenta resistência insulínica. Embora nossos meninos de 5-10 anos tenham se mostrado mais insulino-resistentes que as meninas, e as meninas de 10-16 anos apresentassem maiores valores de HOMA que os meninos, esses dados devem ser confirmados após classificarmos os indivíduos pelos estágios de desenvolvimento sexual de Tanner
