Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104, USA.
Dalton Trans. 2009 Dec 28(48):10882-8. doi: 10.1039/b917792b. Epub 2009 Nov 2.
In this study, we investigate the anticancer properties of an inert half-sandwich metal complex scaffold. UV melting experiments with duplex DNA and (1)H-NMR experiments with 9-ethylguanine reveal that the apoptotic ruthenium complex DW12 does not interact with DNA. On the other hand, diminishing the kinase inhibition properties of DW12 by methylating the maleimide nitrogen (DW12-Me) abolishes the anticancer activity. Furthermore, the incorporation of a fluorine into the pyridine moiety (NP309) improves the IC(50) value for glycogen synthase kinase 3 (GSK-3) and at the same time the cytotoxicity, implying that the anticancer activity correlates with the inhibition of GSK-3 and maybe other not yet identified kinases. We demonstrate in Burkitt-like lymphoma (BJAB) cells that NP309 is not necrotic but induces apoptosis and that this apoptosis is mediated by a loss of the mitochondrial membrane potential, caspase-9 processing, and is partly dependent on Bcl-2 expression. In addition, NP309 efficiently induces apoptosis in vincristine- and cytarabine-resistant human B-cell precursor cell lines.
在这项研究中，我们研究了一种惰性半夹心金属配合物支架的抗癌特性。与双链 DNA 的 UV 熔融实验和 9-乙基鸟嘌呤的 (1)H-NMR 实验表明，凋亡性钌配合物 DW12 不会与 DNA 相互作用。另一方面，通过将马来酰亚胺氮甲基化（DW12-Me）来降低 DW12 的激酶抑制特性，会消除其抗癌活性。此外，在吡啶部分中引入氟原子（NP309）可提高糖原合酶激酶 3（GSK-3）的 IC(50)值，同时也提高了细胞毒性，这表明抗癌活性与 GSK-3 的抑制有关，也许还与其他尚未确定的激酶有关。我们在 Burkitt 样淋巴瘤（BJAB）细胞中证明，NP309 不是坏死性的，而是诱导凋亡，并且这种凋亡是由线粒体膜电位丧失、半胱天冬酶-9 加工介导的，部分依赖于 Bcl-2 表达。此外，NP309 能有效地诱导长春新碱和阿糖胞苷耐药的人 B 细胞前体细胞系凋亡。
