Síntese, caracterização de um complexo metálico de Pt(II) com o inibidor da proteína C-ABL dasatinibe: avaliação da interação com a proteína envolvida na leucemia mieloide crônica

Abstract

This study aimed to develop and characterize a new antitumor agent through the synthesis of a platinum(II) complex with the tyrosine kinase inhibitor, dasatinib (das), aiming to increase the affinity for the BCR-ABL protein, which is central to the pathogenesis of chronic myeloid leukemia (CML). The synthesis was performed by reacting K2PtCl4 with the ligand in methanol, under reflux, in a 1:1 molar ratio. A yellowish solid was obtained with an approximate yield of 80%. Elemental analysis confirmed the proposed stoichiometry for the complex, resulting in experimental percentages of carbon, hydrogen and nitrogen aligned with the values calculated for [Pt(das)Cl₂]. Spectroscopic characterization provided consistent evidence of the formation of the complex. In infrared analysis, free dasatinib presented characteristic bands at 3250cm⁻¹ and 3416cm⁻¹ (associated with stretching of the O–H and N–H groups, respectively), which were shifted to 3220cm⁻¹ and 3406cm⁻¹, respectively, while the stretching of the C=N groups and the thiazole ring underwent shifts to 1548cm⁻¹ and 1486cm⁻¹. These shifts indicated changes in the electronic environment of the coordinating groups, suggesting the participation of the nitrogens of the pyrimidine and thiazole rings in the coordination to Pt(II). Mass spectrometry (ESI-MS) evidenced the formation of the complex with a peak at m/z 754. The interaction of the complex with the BCR-ABL protein was evaluated by circular dichroism and fluorescence spectroscopies. The circular dichroism spectrum revealed that the BCR-ABL protein, in its native form, presents characteristic minima around 208nm and 222nm, indicative of a high content of alpha helices. With the progressive addition of the [Pt(das)Cl₂] complex, a change in the intensity of these minima was observed, due to alterations in the conformational arrangement of the protein. Such changes indicate that the interaction with the complex induces a reorganization in the secondary structure of BCR-ABL, potentially promoting an adjustment that favors the inhibition of tyrosine kinase activity. The results obtained by fluorescence showed a progressive suppression of the emission of the tryptophan residues of the protein and the binding constant of the complex was more than ten times higher than that of free dasatinib. The results indicate that the coordination of Pt(II) ions to dasatinib enhances its ability to interact with the BCR-ABL protein, representing a promising strategy for the development of new anticancer agents capable of overcoming the limitations of traditional treatments for CML, with the potential to reduce cellular resistance and side effects.