Phosphanegold(I) dithiocarbamates, R3PAu[SC(S)N(iPr)CH2CH2OH] for R = Ph, Cy and Et: Role of phosphane-bound R substituents upon in vitro cytotoxicity against MCF-7R breast cancer cells and cell death pathways

• R3PAu[S2CN(iPr)CH2CH2OH], for R = Ph (1), Cy (2) and Et (3), are cytotoxic against MCF-7R breast cancer cells.
• Compound 1 causes apoptosis by both extrinsic and intrinsic pathways; 2 and 3 cause necrosis.
• Compound 1 activates the p53 gene, 2 activates p73, and 3 activates both p53 and p73.
• Compounds 1 and 3 activate NF-κB, and each inhibits topoisomerase I.

The synthesis and characterisation of R3PAu[S2CN(iPr)CH2CH2OH], for R = Ph (1), Cy (2) and Et (3)4, is reported. Compounds 1–3 are cytotoxic against the doxorubicin-resistant breast cancer cell line, MCF-7R, with 1 exhibiting greater potency and cytotoxicity than either of doxorubicin and cisplatin. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis by 1, and necrosis by 2 and 3, are demonstrated, by both extrinsic and intrinsic pathways. Compound 1 activates the p53 gene, 2 activates only the p73 gene, whereas 3 activates both the p53 and p73 genes. Compounds 1 and 3 activate NF-κB, and each inhibits topoisomerase I.

The R3PAu[S2CN(iPr)CH2CH2OH] compounds are cytotoxic to the MCF-7R breast cancer cell line and induce apoptosis/necrosis by both extrinsic and intrinsic pathways.Figure optionsDownload as PowerPoint slide