Síntese e reatividade de complexos de Pt(II) com análogos de purinas: interação com proteínas-alvo e potencial terapêutico contra leucemia mieloide crônica

Abstract

Pt(II) metal complexes play a central role in cancer treatment, however, cellular resistance and side effects limit their success. This work aimed to ally the properties of Pt(II) complexes with those of purine analogs, which block key enzymes involved in DNA and RNA synthesis. Thus, three novel Pt(II) complexes were synthesized with fludarabine, cladribine, and vidarabine, complexes 1, 2, and 3, respectively, and characterized using one- and two-dimensional ¹H NMR, molecular absorption in the UV-Vis, and circular dichroism spectroscopy, confirming the formation of 1:1 complexes through Pt(II) coordination to the N7 of purine analogues. Cytotoxic activity was evaluated in chronic myeloid leukemia cells (K562) and non-cancerous cells (HaCat). Fludarabine and cladribine showed high activity in leukemia cells, as did their Pt(II) complexes, with CI50 values in the range of 8-33 nM, while vidarabine and its complex displayed CI50 in the range of 8-10 μM. The effect of the complexes in the non-cancerous cell line was much lower, with selectivity indices ranging from 120 to 12,000. The uptake of 1 and 2 by K562 cells was monitored by atomic absorption spectrometry, revealing a good correlation between cytotoxic activity and intracellular platinum concentration. All complexes interacted with bovine serum albumin and showed high affinity for the Abl protein, which is associated with the development of chronic myeloid leukemia. The affinity for Abl was approximately 7,000 times higher for complex 1 and 30 times higher for complex 2 than those of the free ligands. This result is extremely relevant since chronic myeloid leukemia is treated with Abl inhibitors, until the appearance of cellular resistance, which limits the success of the therapy. Therefore, the fact that Pt(II) complexes with purine analogues bind to Abl with a much higher affinity than do the drugs currently in use reveals their great therapeutic potential as an alternative treatment for some types of cancer.