Síntese, diversidade estrutural e atividade antitumoral de compostos híbridos uracil-cumarinas

Abstract

The development of new drugs is a long, arduous, and continuum process, which involves a multidisciplinary action and high investments. The discovery of new diseases, tolerance, and resistance acquired by pathogens or tumor cells, as well as the need to minimize the side effects, are some of the reasons for this demand. Organic synthesis plays an essential role in the initial process of developing new bioactive compounds, not only in the design of new structures but also in the modification of existing structures in order to adapt it to the needs of a pharmaceutical compound. In order to optimize the process of obtaining new bioactive molecules, we employed the strategy of molecular hybridization, which consists of the union of two or more pharmacophores in a single molecular skeleton. Thus, we sought to integrate the pharmacological proprieties of two natural molecules, the uracil, and the coumarin, as well as their derivatives, with known biological activities, having the 1,2,3-triazole nucleus as the binding unit. A series of 12 hybrid molecules were synthesized, comprising one unit of uracil, thymine, thiouracil, or theobromine, linked to a variety of coumarin nucleus by triazolic nucleus. The hybrids bis (coumaronyl triazolyl)uracil 7a - b, (coumaronyl-triazolyl)uracil, thymine, thiouracil 8a ? f (coumaronyl triazolyl)theobromine 9a ? d were obtained from a copper-(I)-catalyzed cycloaddition reaction between 4-(azidomethyl)coumarin (4b?d) e 1 propargyluracil 6a, 1-propargylthymine 6b, 2-propargylmercaptouracil 6c, 1,3 dipropargyluracil 6d and 1-propargyltheobromine 6e, with yields of 70 to 92%. The hybrids compounds synthesized were evaluated by their antiproliferative and antitumoral activities against the tumor cell lines (HCT116 - colorectal cancer, A549-lung, and Hep-2 - larynx) and non-tumoral cell line (HaCat - human keratinocytes), in MTT assay. It was found that five of the evaluated compounds (7a-b, 8e, 9a-b) showed cytotoxicity (IC50 <100 ?M) against the HCT116 cell line, and only the compound 7b was cytotoxic against the A549 cell line. The compounds 7a and 9a showed cytotoxicity against Hep2 cell line, and none of the tested compounds showed cytotoxicity against the non-tumor cell line HaCat, even at the highest concentration tested of 100 ?M, at all times evaluated. The in silico toxicity prediction studies were carried out with the compounds 7a-b and 9a-b, which were more promising in the MTT assays. The evaluation showed that all the evaluated compounds showed a low risk of causing theoretical mutagenic and tumorigenic effects. Only compound 7a showed the medium risk to cause an effect on the reproductive system. These results suggest that the target compounds show low potential to cause theoretical toxicity risks, and these can be submitted to drug design development. SEA algorithm was employed based on the hypothesis of identification of candidate target proteins to interact with the compounds 7a-b, and 9a-b. The results indicated the main target model is related to DNA topoisomerase 1. According to these results, this protein was chosen to be used in docking analyses. Docking procedures demonstrated that the carbonyl moiety from coumarin chemical structures of the model generated in these studies showed interaction with HIS 632, while the uracyl interacts with ARG 364 and THR 718. The triazol ring showed interaction with ARG 364 from Topo-1. These results suggest the compounds studied are potential ligands to protein and possible acting as Topo-1 inhibitors [resumo fornecido pelo autor].