Olar Rodica, Maxim Catalin, Badea Mihaela, Bacalum Mihaela, Raileanu Mina, Avram Speranta, Korošin Nataša Čelan, Burlanescu Teodora, Rostas Arpad Mihai
Faculty of Chemistry, Department of Inorganic Chemistry, University of Bucharest, 90-92 Panduri Str., 050663 Bucharest, Romania.
Horia Hulubei National Institute for Physics and Nuclear Engineering, Department of Life and Environmental Physics, 30 Reactorului Str., 077125 Magurele-Ilfov, Romania.
Pharmaceutics. 2022 Aug 14;14(8):1692. doi: 10.3390/pharmaceutics14081692.
Melanoma is a skin cancer characterized by rapid growth and spread for which current therapies produce both resistance and increased risk of infection. To develop new anti-melanoma biocompatible species, the series of complexes Cu(N-N)(bzac)(X)⋅nHO (N-N: 1,10-phenanthroline/2,2'-bipyridine, Hbzac: 1-phenyl-1,3-butanedione, X: NO/ClO, and = 0, 1) was studied. Single-crystal X-ray diffraction revealed a mononuclear structure for all complexes. The ability of the complexes to scavenge or trap reactive oxygen species such as O⋅ and HO⋅ was proved by EPR spectroscopy experiments. All complexes inhibited B16 murine melanoma cells in a dose-dependent and nanomolar range, but the complexes with 1,10-phenanthroline were more active. Moreover, comparative activity on B16 and healthy BJ cells revealed a therapeutic index of 1.27-2.24. Bioinformatic methods were used to calculate the drug-likeness, pharmacokinetic, pharmacogenomic, and pharmacodynamic profiles of the compounds. The results showed that all compounds exhibit drug-likeness features, as well as promising absorption, distribution, metabolism, and excretion (ADME) properties, and no toxicity. The pharmacodynamics results showed that the neutral species appear to be good candidates for antitumor molecular targets (Tyrosyl-DNA phosphodiesterase 1, DNA-(apurinic or apyrimidinic site) lyase or Kruppel-like factor 5). Furthermore, the pharmacogenomic results showed a good affinity of the copper(II) complexes for the human cytochrome. These results recommend complexes bearing 1,10-phenanthroline as good candidates for developing drugs to melanoma alternative treatment.
黑色素瘤是一种以快速生长和扩散为特征的皮肤癌，目前的治疗方法会产生耐药性并增加感染风险。为了开发新的抗黑色素瘤生物相容性物种，研究了一系列配合物Cu(N-N)(bzac)(X)⋅nH₂O（N-N：1,10-菲咯啉/2,2'-联吡啶，Hbzac：1-苯基-1,3-丁二酮，X：NO₃⁻/ClO₄⁻，且n = 0, 1）。单晶X射线衍射揭示了所有配合物的单核结构。电子顺磁共振光谱实验证明了这些配合物清除或捕获活性氧物种（如O₂⁻和HO⋅）的能力。所有配合物在纳摩尔范围内呈剂量依赖性抑制B16小鼠黑色素瘤细胞，但含1,10-菲咯啉的配合物活性更高。此外，对B16细胞和健康BJ细胞的比较活性显示治疗指数为1.27 - 2.24。采用生物信息学方法计算了这些化合物的类药性、药代动力学、药物基因组学和药效学特征。结果表明，所有化合物均表现出类药性特征，以及良好的吸收、分布、代谢和排泄（ADME）特性，且无毒性。药效学结果表明，中性物种似乎是抗肿瘤分子靶点（酪氨酰-DNA磷酸二酯酶1、DNA-（无嘌呤或无嘧啶位点）裂解酶或Kruppel样因子5）的良好候选物。此外，药物基因组学结果显示铜（II）配合物对人细胞色素具有良好的亲和力。这些结果表明，含1,10-菲咯啉的配合物是开发黑色素瘤替代治疗药物的良好候选物。
