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Toward a Rational Design of Polyamine-Based Zinc-Chelating Agents for Cancer Therapies.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-14 , DOI: 10.1021/acs.jmedchem.9b01554 Cristina Galiana-Roselló 1, 2 , Clara Aceves-Luquero 3 , Jorge González 1 , Álvaro Martínez-Camarena 1 , Ruth Villalonga 4 , Silvia Fernández de Mattos 3, 5 , Concepción Soriano 6 , José Llinares 6 , Enrique García-España 1 , Priam Villalonga 3 , María Eugenia González-Rosende 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-14 , DOI: 10.1021/acs.jmedchem.9b01554 Cristina Galiana-Roselló 1, 2 , Clara Aceves-Luquero 3 , Jorge González 1 , Álvaro Martínez-Camarena 1 , Ruth Villalonga 4 , Silvia Fernández de Mattos 3, 5 , Concepción Soriano 6 , José Llinares 6 , Enrique García-España 1 , Priam Villalonga 3 , María Eugenia González-Rosende 2
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In vitro viability assays against a representative panel of human cancer cell lines revealed that polyamines L1a and L5a displayed remarkable activity with IC50 values in the micromolar range. Preliminary research indicated that both compounds promoted G1 cell cycle arrest followed by cellular senescence and apoptosis. The induction of apoptotic cell death involved loss of mitochondrial outer membrane permeability and activation of caspases 3/7. Interestingly, L1a and L5a failed to activate cellular DNA damage response. The high intracellular zinc-chelating capacity of both compounds, deduced from the metal-specific Zinquin assay and ZnL2+ stability constant values in solution, strongly supports their cytotoxicity. These data along with quantum mechanical studies have enabled to establish a precise structure-activity relationship. Moreover, L1a and L5a showed appropriate drug-likeness by in silico methods. Based on these promising results, L1a and L5a should be considered a new class of zinc-chelating anticancer agents that deserves further development.
中文翻译：
走向合理设计基于多胺的锌螯合剂用于癌症治疗。
针对人类癌细胞系代表小组的体外生存力分析表明，多胺L1a和L5a表现出显着的活性，其IC50值在微摩尔范围内。初步研究表明，这两种化合物均能促进G1细胞周期阻滞，进而促进细胞衰老和凋亡。凋亡细胞的诱导涉及线粒体外膜通透性的丧失和胱天蛋白酶3/7的激活。有趣的是，L1a和L5a无法激活细胞DNA损伤反应。从金属特异性Zinquin测定法和溶液中ZnL2 +稳定常数值推论得出，这两种化合物的高细胞内锌螯合能力均强烈支持其细胞毒性。这些数据以及量子力学研究已经能够建立精确的结构-活性关系。此外，L1a和L5a通过计算机方法显示出适当的药物相似性。基于这些有希望的结果，L1a和L5a应该被认为是一类值得进一步发展的新型锌螯合抗癌剂。
更新日期：2020-01-26
中文翻译：
走向合理设计基于多胺的锌螯合剂用于癌症治疗。
针对人类癌细胞系代表小组的体外生存力分析表明，多胺L1a和L5a表现出显着的活性，其IC50值在微摩尔范围内。初步研究表明，这两种化合物均能促进G1细胞周期阻滞，进而促进细胞衰老和凋亡。凋亡细胞的诱导涉及线粒体外膜通透性的丧失和胱天蛋白酶3/7的激活。有趣的是，L1a和L5a无法激活细胞DNA损伤反应。从金属特异性Zinquin测定法和溶液中ZnL2 +稳定常数值推论得出，这两种化合物的高细胞内锌螯合能力均强烈支持其细胞毒性。这些数据以及量子力学研究已经能够建立精确的结构-活性关系。此外，L1a和L5a通过计算机方法显示出适当的药物相似性。基于这些有希望的结果，L1a和L5a应该被认为是一类值得进一步发展的新型锌螯合抗癌剂。
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