Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
Institute of Parasitology Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland.
Molecules. 2023 Jan 16;28(2):902. doi: 10.3390/molecules28020902.
Eight novel carbohydrate-tethered trithiolato dinuclear ruthenium(II)-arene complexes were synthesized using CuAAC ‘click’ (Cu(I)-catalyzed azide-alkyne cycloaddition) reactions, and there in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) and in non-infected human foreskin fibroblasts, HFF, was determined at 0.1 and 1 µM. When evaluated at 1 µM, seven diruthenium-carbohydrate conjugates strongly impaired parasite proliferation by >90%, while HFF viability was retained at 50% or more, and they were further subjected to the half-maximal inhibitory concentration (IC50) measurement on T. gondii β-gal. Results revealed that the biological activity of the hybrids was influenced both by the nature of the carbohydrate (glucose vs. galactose) appended on ruthenium complex and the type/length of the linker between the two units. 23 and 26, two galactose-based diruthenium conjugates, exhibited low IC50 values and reduced effect on HFF viability when applied at 2.5 µM (23: IC50 = 0.032 µM/HFF viability 92% and 26: IC50 = 0.153 µM/HFF viability 97%). Remarkably, compounds 23 and 26 performed significantly better than the corresponding carbohydrate non-modified diruthenium complexes, showing that this type of conjugates are a promising approach for obtaining new antiparasitic compounds with reduced toxicity.
合成了 8 种新型糖基三硫代二核钌（II）-芳烃配合物，利用 CuAAC“点击”（Cu（I）催化叠氮-炔烃环加成）反应，在 0.1 和 1µM 时测定了它们对表达β-半乳糖苷酶（T. gondii β-gal）的转基因弓形虫速殖子和未感染的人包皮成纤维细胞（HFF）的体外活性。当评估浓度为 1µM 时，7 种二钌-糖基缀合物强烈抑制寄生虫增殖超过 90%，而 HFF 存活率保持在 50%或更高，并且它们进一步进行了半最大抑制浓度（IC50）对 T. gondii β-gal 的测定。结果表明，杂交物的生物活性既受糖（葡萄糖与半乳糖）在钌络合物上的性质影响，也受两个单元之间连接体的类型/长度影响。23 和 26 两种基于半乳糖的二钌缀合物，在 2.5µM 时表现出低的 IC50 值和对 HFF 存活率的影响较小（23：IC50=0.032µM/HFF 存活率 92%，26：IC50=0.153µM/HFF 存活率 97%）。值得注意的是，化合物 23 和 26 的性能明显优于相应的非糖基化二钌配合物，表明这类缀合物是获得毒性降低的新型抗寄生虫化合物的一种很有前途的方法。
