Estudo in silico, síntese e avaliação in vitro de novos derivados acridínicos com possível ação antitumoral

Abstract

In the search for new chemotherapeutics, the synthesis of compounds containing aromatic groups and planar regions, such as acridine derivatives, is a simple and economical alternative and therefore, these molecules are being widely studied as possible chemotherapeutics. The objective of this work was to synthesize new acridine derivatives, to elucidate their structures and to evaluate the antitumor potential in silico and in vitro. The synthesis of the compounds occurred linearly and the carbothioamide intermediates were synthesized initially, followed by a coupling reaction with 9-chloroacridine to obtain the final compounds. Molecular structures were submitted to molecular minimization techniques (MM2) and analyzed by molecular docking to initially verify the interaction with TopoIIα/DNA (5GWK) and B-DNA (1BNA), after which the anchoring with two more enzymes, Bcl-2 (4AQ3) and BSA (4OR0). In vitro tests were performed to evaluate the interaction with ctDNA and BSA, and antiproliferative activity against MCF-7 (breast cancer), HL-60 (acute promyelocytic leukemia) and HCT 116 (colon cancer) cell lines. Target prediction studies and pharmacokinetic studies were also conducted through the SwissADME server. Synthesis was carried out with variation of the reaction conditions to verify the obtaining of product different from the one obtained and to optimize the synthetic route, being adopted a factorial design 23 with repetition in the best result obtaining 09 experiments, which was obtained better through the experiment with solvent Propanol, with a temperature of 0 ºC and absence of catalyst. ADME studies demonstrated that ACW-01B showed high gastrointestinal absorption. In relation to molecular docking, ACW 02B was the one that presented the best interaction for the enzymes tested, except for Bcl-2, an enzyme present in breast cancer, which ACW-01B showed the highest interaction (-7.27 kcal mol^-1). In in silico DNA interaction studies ACW-02B presented better interaction result (1.17 x 10^6), however the same compound showed hyperchromicity indicating that the interaction does not occur by intercalation. In the in silico tests of interaction with the BSA, the ACW-01B was the compound that presented the best results with Ksv of 8.4 x 10^4, besides presenting 61% hypochromic effect. In the antiproliferative activity tests ACW-01B was the most active compound, except for the MCF-7 strain which could not be read due to the intense reddish coloration of the compound mentioned, and in this way 2 acridine triazolidinic derivatives were obtained which were submitted to molecular docking where the compounds presented considerable interactions with emphasis on ACW-01B against Bcl-2 enzyme, which stood out in relation to ACW-02B, corroborating with in vitro tests with solid tumor cell lines such as observed in the HCT 116 (colon cancer) test.