Universidad de Alcalá, Instituto de Investigación Química "Andrés M. del Río" (IQAR), Departamento de Química Orgánica y Química Inorgánica, 28805 Alcalá de Henares, Madrid, Spain.
Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Biología de Sistemas, 28805 Alcalá de Henares, Madrid, Spain.
J Inorg Biochem. 2023 Oct;247:112326. doi: 10.1016/j.jinorgbio.2023.112326. Epub 2023 Jul 13.
Novel water-soluble half-sandwich ruthenium(II) polypyridyl-glycoconjugates [Ru(p-cymene)Cl{N-(1,10-phenanthroline-5-yl)-β-glycopyranosylamine}][Cl] (glycopyranosyl = d-glucopyranosyl (1), D-mannopyranosyl (2), L-rhamnopyranosyl (3) and l-xylopyranosyl (4)) have been synthesized and fully characterized. Their behaviour in water under physiological conditions has been studied by nuclear magnetic resonance spectroscopy, revealing their hydrolytic stability. Interactions of the novel compounds with duplex-deoxiribonucleic acid (dsDNA) were investigated by different techniques and the results indicate that, under physiological pH and saline conditions, the metal glycoconjugates bind DNA in the minor groove and/or through external, electrostatic interactions, and by a non-classical, partial intercalation mechanism in non-saline phosphate buffered solution. Effects of compounds 1-4 on cell viability have been assessed in vitro against two human cell lines (androgen-independent prostate cancer PC-3 and non-tumorigenic prostate RWPE-1), showing moderate cytotoxicities, with IC values higher than those found for free ligands [N-(1,10-phenanthroline-5-yl)-β-glycopyranosylamine] (glycopyranosyl = d-glucopyranosyl (a), D-mannopyranosyl (b), L-rhamnopyranosyl (c) and l-xylopyranosyl (d)) or corresponding metal-aglycone. Cell viability was assayed in the presence and absence of the glucose transporters (GLUTs) inhibitor [N-{1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dicarboxamide] (BAY-876), and the results point to a negligible impact of the inhibition of GLUTs on the cytotoxicity caused by Ru(II) compounds 1-4. Remarkably, glycoconjugates 1-4 potently affect the migration pattern of PC-3 cells, and the wound healing assay evidence that the presence of the carbohydrate and the Ru(II) center is a requisite for the anti-migratory activity observed in these novel derivatives. In addition, derivatives 1-4 strongly affect the matrix metalloproteinase MMP-9 activities of PC-3 cells, while proMMP-2 and especially proMMP-9 were influenced to a much lesser extent.
新型水溶性半三明治钌（II）多吡啶糖缀合物[Ru(p-cymene)Cl{N-(1,10-菲咯啉-5-基)-β-吡喃葡萄糖胺}][Cl]（吡喃葡萄糖基= D-吡喃葡萄糖基（1）、D-吡喃甘露糖基（2）、L-鼠李吡喃糖基（3）和 L-吡喃木糖基（4））已被合成并进行了全面表征。通过核磁共振波谱研究了它们在生理条件下在水中的水解稳定性。采用不同技术研究了新型化合物与双链脱氧核糖核酸（dsDNA）的相互作用，结果表明，在生理 pH 值和盐条件下，金属糖缀合物通过小沟结合 DNA 和/或通过外部静电相互作用，以及在非盐磷酸盐缓冲溶液中通过非经典的部分嵌入机制结合 DNA。在体外针对两种人类细胞系（雄激素非依赖性前列腺癌 PC-3 和非肿瘤前列腺 RWPE-1）评估了化合物 1-4 对细胞活力的影响，结果表明它们具有中等的细胞毒性，IC 值高于游离配体[N-(1,10-菲咯啉-5-基)-β-吡喃葡萄糖胺]（吡喃葡萄糖基= D-吡喃葡萄糖基（a）、D-吡喃甘露糖基（b）、L-鼠李吡喃糖基（c）和 L-吡喃木糖基（d））或相应的金属去糖基。在存在和不存在葡萄糖转运蛋白（GLUTs）抑制剂[N- {1-（4-氰基苄基）-5-甲基-3-（三氟甲基）-1H-吡唑-4-基}-7-氟喹啉-2,4-二羧酸酰胺]（BAY-876）的情况下，测定了细胞活力，结果表明 GLUTs 的抑制对 Ru(II)化合物 1-4 引起的细胞毒性影响可以忽略不计。值得注意的是，糖缀合物 1-4 强烈影响 PC-3 细胞的迁移模式，伤口愈合试验表明，碳水化合物和 Ru(II)中心的存在是观察到这些新型衍生物的抗迁移活性所必需的。此外，衍生物 1-4 强烈影响 PC-3 细胞基质金属蛋白酶 MMP-9 的活性，而 proMMP-2 和特别是 proMMP-9 受到的影响要小得多。
