Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal; Centro de Química Estrutural (CQE), Institute of Molecular Sciences, Departamento de Engenharia Química, Instituto Superior Técnico (IST), Universidade de Lisboa, Lisboa 1049-001, Portugal.
Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal.
J Inorg Biochem. 2024 Feb;251:112436. doi: 10.1016/j.jinorgbio.2023.112436. Epub 2023 Nov 23.
The successful choice of hit compounds during drug development programs involves the integration of structure-activity relationship (SAR) studies with pharmacokinetic determinations, including metabolic stability assays and metabolite profiling. A panel of nine ruthenium-cyclopentadienyl (RuCp) compounds with the general formula [Ru(η-CHR)(PPh)(bipyR')] (with R = H, CHO, CHOH; R' = H, CH, CHOH, CHBiotin) has been tested against hormone-dependent MCF-7 and triple negative MDA-MB-231 breast cancer cells. In general, all compounds showed important cytotoxicity against both cancer cell lines and were able to inhibit the formation of MDA-MB-231 colonies in a dose-dependent manner, while showing selectivity for cancer cells over normal fibroblasts. Among them, four compounds stood out as lead structures to be further studied. Cell distribution assays revealed their preference for the accumulation at cell membrane (Ru quantification by ICP-MS) and the mechanism of cell death seemed to be mediated by apoptosis. Potential structural liabilities of lead compounds were subsequently flagged upon in vitro metabolic stability assays and metabolite profiling. The implementation of this integrated strategy led to the selection of RT151 as a promising hit compound.
在药物开发项目中，成功选择命中化合物涉及将结构-活性关系 (SAR) 研究与药代动力学测定相结合，包括代谢稳定性测定和代谢产物分析。一组具有通式 [Ru(η-CHR)(PPh)(bipyR')] 的九种钌-环戊二烯基 (RuCp) 化合物（其中 R = H、CHO、CHOH；R' = H、CH、CHOH、CHBiotin）已针对激素依赖性 MCF-7 和三阴性 MDA-MB-231 乳腺癌细胞进行了测试。总的来说，所有化合物对两种癌细胞系均显示出重要的细胞毒性，并能够以剂量依赖性方式抑制 MDA-MB-231 集落的形成，同时对癌细胞表现出选择性，而对正常成纤维细胞则没有毒性。其中，有四种化合物作为进一步研究的先导结构脱颖而出。细胞分布测定表明它们优先积累在细胞膜上（通过 ICP-MS 对 Ru 进行定量），细胞死亡的机制似乎是通过凋亡介导的。随后在体外代谢稳定性测定和代谢产物分析中标记了先导化合物的潜在结构缺陷。这种综合策略的实施导致选择 RT151 作为有前途的命中化合物。
