Laboratorio de Organocatálisis Asimétrica, Departamento de Química Orgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza, C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain.
Laboratorio de Organocatálisis Asimétrica, Departamento de Química Orgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza, C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain; Departamento de Química Inorgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza, C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain; Departamento de Imagen y Fenotipado, Instituto Aragonés de Ciencias de la Salud, Centro de Investigación Biomédica de Aragón (CIBA), Avda. San Juan Bosco, 13, planta D, E-50009 Zaragoza, Spain.
Bioorg Chem. 2020 Dec;105:104364. doi: 10.1016/j.bioorg.2020.104364. Epub 2020 Oct 10.
In this work, the synthesis of interesting urea derivatives 5 based on 1,4-dihydropyridines 3 is described for the first time. Considering that both families exhibit potential as drugs to treat various diseases, their activity as anticancer agents has been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice in vivo. In general, whereas 1,4-dihydropyridines show a moderate cytotoxic activity, their urea analogues cause an extraordinary increase in their antiproliferative activity, specially towards HeLa cells. Because of the chiral nature of these compounds, enantiomerically enriched samples were also tested, showing different cytotoxic activity than the racemic mixture. Although the reason is not clear, it could be caused by a complex amalgam of physical and chemical contributions. The studied compounds also exhibit luminescent properties, which allow performing a biodistribution study in cancer cells. They have emission maxima between 420 and 471 nm, being the urea derivatives in general red shifted. Emission quenching was observed for those compounds containing a nitro group (3e,f and 5e,f). Fluorescence microscopy showed that 1,4-dihydropyridines 3a and 3g localised in the lysosomes, in contrast to the urea derivatives 5h that accumulated in the cell membrane. This different distribution could be key to explain the differences found in the cytotoxic activity and in the mechanism of action. Interestingly, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC value. No downgrade in the welfare of the tested mice was observed, which could support their use in preclinical tumour models.
在这项工作中，首次描述了基于 1,4-二氢吡啶 3 的有趣的尿素衍生物 5 的合成。考虑到这两个家族都有可能作为治疗各种疾病的药物，因此评估了它们作为抗癌剂在 HeLa（宫颈）、Jurkat（白血病）和 A549（肺癌）癌细胞系以及体内健康小鼠中的活性。一般来说，虽然 1,4-二氢吡啶显示出中等的细胞毒性活性，但它们的尿素类似物导致其增殖活性显著增加，特别是对 HeLa 细胞。由于这些化合物的手性性质，还测试了对映体富集的样品，它们表现出与外消旋混合物不同的细胞毒性活性。尽管原因尚不清楚，但可能是由于物理和化学因素的复杂混合所致。所研究的化合物还具有发光性质，这允许在癌细胞中进行生物分布研究。它们的发射最大值在 420 和 471nm 之间，尿素衍生物通常红移。观察到含有硝基基团的化合物（3e、f 和 5e、f）发生荧光猝灭。荧光显微镜显示，1,4-二氢吡啶 3a 和 3g 定位于溶酶体中，而尿素衍生物 5h 则积累在细胞膜中。这种不同的分布可能是解释在细胞毒性活性和作用机制中发现的差异的关键。有趣的是，对一些化合物在健康小鼠体内的急性毒性进行了初步的体内研究，使用的浓度比相应的 IC 值高 7200 倍。未观察到测试小鼠福利下降，这可能支持它们在临床前肿瘤模型中的应用。
