Laboratory of Natural and Synthetics Products, Biotechnology Institute, University of Caxias do Sul, Caxias do Sul, RS CEP: 95070-560, Brazil.
Department of Energy and Sustentability, Araranguá Center, Federal University of Santa Catarina, Rod. Gov. Jorge Lacerda, 3201 Jardim das Avenidas, Araranguá, SC CEP: 88.906-072, Brazil.
J Inorg Biochem. 2020 May;206:111046. doi: 10.1016/j.jinorgbio.2020.111046. Epub 2020 Feb 20.
In the search for new drugs, strategies such as bioisosterism have been evidenced, in which the modification of molecules is already known to be active. Thus, metal complexes of known drugs have been highlighted, with examples of significant improvements in therapeutic efficacy. In this way, this work aimed at the synthesis of new zinc complexes with nonsteroidal anti-inflammatory drugs (NSAIDs), as well as the chemical characterization and the previous toxicity by cytotoxicity with Artemia salina, and evaluating the ability of these compounds to interact with DNA. As result, two new zinc II ternary complexes containing the NSAIDs diclofenac (Diclof) and ibuprofen (Ibup) and nicotinamide neutral linker (Nic) were obtained by the two-step solvent metal-ligand complexation method. Molecular structures were determined by NMR, FTIR, HR-MS, UV-Vis and X-ray diffraction, which demonstrated that both complexes are binuclear systems of general formula [Zn(R-COO)(Nic)]. Plasmidial DNA breakdown capacities were evaluated by producing single and double breaks (DNA FII and FIII) from plasmid incubation with complex solutions in the concentration range 0 to 400 μmol·L in experiments with the presence and absence of light. Both experiments did not show significant differences (P ≤ 0.05) in induced DNA cleavage activity between the maximum study concentrations (400 μmol·L) and the negative controls for both complexes. The types of complex 1 and 2 interactions with the secondary DNA structure were determined by titrating a CT-DNA solution with complex solutions and monitored by circular dichroism spectrometry. The results showed that both complexes interact with the grooves of the secondary structure of CT-DNA by electrostatic attraction, but without evidence of alteration in the primary structure. Acute toxicity tests against Artemia salina showed that both complexes did not produce lethality >10% of the population up to a maximum concentration of 1200 μg·mL within an exposure interval of 24 h. Thus, two new compounds were synthesized, characterized and had their previous toxicities determined. These compounds are promising new drugs, with the next step being evaluations of their activity.
在寻找新药的过程中，已经证实了生物等排策略，其中分子的修饰已经被证明是有效的。因此，已经突出了已知药物的金属配合物的例子，这些例子表明治疗效果有了显著提高。通过这种方式，这项工作旨在合成新的含非甾体抗炎药（NSAIDs）的锌配合物，以及通过卤虫进行细胞毒性的化学表征和毒性前体测试，并评估这些化合物与 DNA 相互作用的能力。结果，通过两步溶剂金属-配体络合方法获得了两种含有非甾体抗炎药双氯芬酸（Diclof）和布洛芬（Ibup）和烟酰胺中性连接体（Nic）的新型锌 II 三元配合物。通过 NMR、FTIR、HR-MS、UV-Vis 和 X 射线衍射确定了分子结构，结果表明这两种配合物都是通用式[Zn（R-COO）（Nic）]的双核体系。通过在浓度范围为 0 至 400 μmol·L 的复杂溶液孵育质粒来评估质粒 DNA 断裂能力，在有光和无光的实验中产生单链和双链断裂（DNA FII 和 FIII）。在最大研究浓度（400 μmol·L）和两种复合物的阴性对照之间，两种实验都没有显示出诱导 DNA 切割活性的显著差异（P ≤ 0.05）。通过用复合物溶液滴定 CT-DNA 溶液并通过圆二色性光谱监测，确定了复合物 1 和 2 与二级 DNA 结构的相互作用类型。结果表明，两种复合物都通过静电吸引与 CT-DNA 二级结构的沟槽相互作用，但没有证据表明一级结构发生改变。对卤虫的急性毒性试验表明，两种复合物在 24 小时的暴露间隔内，最高浓度达到 1200 μg·mL 时，不会产生致死率>10%的种群。因此，合成了两种新的化合物，并对其进行了表征和毒性前体的测定。这些化合物是有前途的新药，下一步是评估它们的活性。
