Costas-Lago María Carmen, Vila Noemí, Rahman Adeyemi, Besada Pedro, Rozas Isabel, Brea José, Loza María Isabel, González-Romero Elisa, Terán Carmen
Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, España.
Instituto de Investigación Sanitaria Galicia Sur, Hospital Álvaro Cunqueiro, 36213 Vigo, España.
ACS Med Chem Lett. 2022 Feb 10;13(3):463-469. doi: 10.1021/acsmedchemlett.1c00633. eCollection 2022 Mar 10.
Novel aryl guanidinium analogues containing the pyridazin-3(2)-one core were proposed as minor groove binders (MGBs) with the support of molecular docking studies. The target dicationic or monocationic compounds, which show the guanidium group at different positions of the pyridazinone moiety, were synthesized using the corresponding silyl-protected pyridazinones as key intermediates. Pyridazinone scaffolds were converted into the adequate bromoalkyl derivatives, which by reaction with ,'-di-Boc-protected guanidine followed by acid hydrolysis provided the hydrochloride salts - in good yields. The ability of new pyridazin-3(2)-one-based guanidines as DNA binders was studied by means of DNA UV-thermal denaturation experiments. Their antiproliferative activity was also explored in three cancer cell lines (NCI-H460, A2780, and MCF-7). Compounds - with a bis-guanidinium structure display a weak DNA binding affinity and exhibit a reasonable cellular viability inhibition percentage in the three cancer cell lines studied.
在分子对接研究的支持下，含有哒嗪-3(2)-酮核心的新型芳基胍类似物被提出作为小沟结合剂（MGBs）。以相应的硅烷基保护的哒嗪酮为关键中间体，合成了在哒嗪酮部分不同位置显示胍基的目标双阳离子或单阳离子化合物。哒嗪酮支架被转化为合适的溴代烷基衍生物，该衍生物与双-Boc保护的胍反应，然后进行酸水解，得到盐酸盐，产率良好。通过DNA紫外热变性实验研究了新型基于哒嗪-3(2)-酮的胍作为DNA结合剂的能力。还在三种癌细胞系（NCI-H460、A2780和MCF-7）中探索了它们的抗增殖活性。具有双胍结构的化合物显示出较弱的DNA结合亲和力，并且在所研究的三种癌细胞系中表现出合理的细胞活力抑制百分比。
