UC Santa Barbara

A novel Ru-based anticancer agent was developed for the treatment of triple negative breast cancer via combination of cytotoxic and anti-metastatic activities within a single molecular platform. Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with high metastatic potential and limited treatment options. Herein, we developed a dual-function anticancer agent RuSPDTC ([Ru 2 (μ-N)(NH 3 ) 8 (S 2 CN(CH 2 ) 4 )] 3+ ) by attaching the cytotoxic pyrrolidine dithiocarbamate (PDTC) ligand to the mitochondrial calcium uniporter (MCU) inhibitor Ru265 ([Ru 2 (μ-N)(NH 3 ) 8 Cl 2 ] 3+ ). RuSPDTC combines the anti-metastatic activity of MCU inhibition with PDTC-mediated cytotoxicity within a single molecular platform. RuSPDTC was synthesized and characterized by multinuclear NMR spectroscopy, HR-ESI-MS, FTIR spectroscopy, UV-vis spectroscopy, and single-crystal X-ray diffraction. The 13 C resonance of the CS 2 group showed an upfield shift of the coordinated PDTC ligands, and HR-ESI-MS revealed an m / z of [M − CF 3 SO 3 ] + at 943.9475 Da. These data confirmed the coordination of PDTC to the Ru265 scaffold. The crystal structure of RuSPDTC showed that PDTC coordinates to Ru through S at the axial positions, representing the first Ru265 analogue featuring an S-donor ligand. UV-vis kinetic studies demonstrated its aquation under physiological conditions with a half-life of 2.4 h, leading to the quantitative release of bioactive Ru265′ ([Ru 2 (μ-N)(NH 3 ) 8 (OH 2 ) 2 ] 5+ ) and two equivalents of PDTC. Within MDA-MB-231 TNBC cells, RuSPDTC exhibited potent Cu 2+ -dependent cytotoxicity with an IC 50 value of 0.07 μM in the presence of 10 μM Cu 2+ , a value that is two orders of magnitude smaller than that in the absence of Cu 2+ . Importantly, RuSPDTC retained potent MCU-inhibitory activity with an IC 50 value of 4.23 nM and effectively suppressed cancer cell invasion and migration. Overall, this work establishes a proof-of-concept study for developing dual-function Ru265-based therapeutics integrating cytotoxic and anti-metastatic activities into a single scaffold through incorporation of bioactive ligands.