Síntese e avaliação do potencial antitumoral de novos derivados tiossemicarbazônicos-acridínicos

Abstract

Cancer is a serious global public health problem. The acridine derivatives more known in the clinic is amsacrine, however, has side effects that make the study and structural modification of this compound completely viable. A class of small molecules, the thiosemicarbazides, has been studied with various biological activities reported. Based on the Method of Topliss to overrides in derived from the thiosemicarbazides intermediaries, we conducted a study of molecular docking with acridine-thiosemicarbazone compounds-substituted, demonstrating promising results with the drug Etoposide as a reference. With a focus on planning of new derivatives with potential antitumor activity, synthesis and evaluation, in silico and in vitro, were held. Twelve new derivatives were synthesized and characterized by techniques such as infrared-IV, nuclear magnetic resonance, 1 d and 2D NMR, mass spectroscopy and ultraviolet visible. The compounds showed incomes between 60 and 96%, with 1 the fusion range 4° C. Studies of interaction of compounds with DNA and BSA were carried out in vitro and, corroborate the idea suggested by docking capability. The derived GLDL-02 presented greater interaction with DNA, Kb = 1.91 x 10^7 M^-1, assuming a strong interaction to the groove. The compound GLDL-01 has been shown to have greater affinity for the protein BSA, with Ksv = 2.17 x 10^5. The cytotoxicity of the derivatives front of leukemia cells, HL-60, breast cancer, MCF-7 and HCT, colon cancer, were evaluated with moderate results, the derived GLCL-04 showed inhibition of 83.7% compared to cells HL-60 at a concentration of 50 µM against the MCF-7 cells and HCT, the new derivatives were less cytotoxic, as shown by the inhibition GLCL-01, 56% to MCF-7, and-03 GLCL, 66.86% for HCT. Planning from Topliss tree was confronted with the results of biological activity for new derivatives, confirming that the necessary structural modifications influenced the biological responses in vitro by following your proposal. Cytotoxicity in plasma cells evaluated by hemolysis testing demonstrated that the derivatives did not influence to cell lysis. Pharmacokinetic predictions were made for ADME properties and knowledge of metabolism of new acridine-thiosemicarbazone derivatives. The GLCL derivatives, the unsubstituted acridine nucleus, were not generally more potent as cell waves, but the lower percentages of interaction with DNA and BSA that are derived from the GLDL series. The results corroborate to the idea that the main mechanism in the cell lines studied is not the interaction with DNA, and studies of other possible mechanisms should be considered to better understand the activities found. Studies like the interaction with topoisomerase and test in other neoplasic cell lines will be carried out to confirm the power of the new derivatives.