Potent Ruthenium–Ferrocene Bimetallic Antitumor Antiangiogenic Agent That Circumvents Platinum Resistance: From Synthesis and Mechanistic Studies to In Vivo Evaluation in Zebrafish

Abstract

Emergence of resistance in cancer cells and dose-limiting side effects severely limit the widespread use of platinum (Pt) anticancer drugs. Multiaction hybrid anticancer agents that are constructed by merging two or more pharmacophores offer the prospect of circumventing issues of Pt drugs. Herein, we report the design, synthesis, and in-depth biological evaluation of a ruthenium− ferrocene (Ru-Fc) bimetallic agent [(η 6 -p-cymene)Ru(1,1,1-trifluoro-4-oxo-4ferrocenyl-but-2-en-2-olate)Cl] and its five analogues. Along with aquation/ anation chemistry, we evaluated the in vitro antitumor potency, Pt cross-resistance profile, and in vivo antiangiogenic properties. A structure activity analysis was performed to understand the impact of Fc, CF 3 , and p-cymene groups on the anticancer potency of the Ru-Fc hybrid. Finally, in addition to assessing cellular uptake and intracellular distribution, we demonstrated that the Ru-Fc hybrid binds to nucleophilic biomolecules and produces reactive oxygen species, which causes mitochondrial dysfunction and induces ER stress, leading to poly(ADP−ribose) polymerasemediated necroptotic cell death.

The Power of Kinetic Inertness in Improving Platinum Anticancer Therapy by Circumventing Resistance and Ameliorating Nephrotoxicity

“…Chemie through mitochondrial dysfunction (discussed later), the IC 50 value of 4 was redetermined in HeLa cells using crystal violet (CV) assay, an enzyme independent assay that reports the viability by measuring biomass of adherent cells. [16] The IC 50 value 0.20 μM obtained from CV assay (Figure S17) is comparable to that obtained from MTT assay (0.16 μM). Consistent with the results on HeLa cells, our best derivative 4 turned out to be 14-and 13-times more potent as compared to cisplatin on HT29 colon (IC 50 = 0.38 μM for 4 and 5.5 μM for cisplatin) and SKOV3 ovarian (IC 50 = 0.56 μM for 4 and 7.4 μM for cisplatin) cancer cells, which are poorly sensitive to Pt drugs (Table S1, Figure S18 for dose-response plots).…”

“…The IC 50 value obtained using the commonly employed MTT assay reflects the effect of a compound on mitochondrial dehydrogenase activity rather than the effect on viability. As 4 exerts antitumor activity through mitochondrial dysfunction (discussed later), the IC 50 value of 4 was redetermined in HeLa cells using crystal violet (CV) assay, an enzyme independent assay that reports the viability by measuring biomass of adherent cells [16] . The IC 50 value 0.20 μM obtained from CV assay (Figure S17) is comparable to that obtained from MTT assay (0.16 μM).…”

The Power of Kinetic Inertness in Improving Platinum Anticancer Therapy by Circumventing Resistance and Ameliorating Nephrotoxicity

“…through mitochondrial dysfunction (discussed later), the IC 50 value of 4 was redetermined in HeLa cells using crystal violet (CV) assay, an enzyme independent assay that reports the viability by measuring biomass of adherent cells. [16] The IC 50 value 0.20 μM obtained from CV assay (Figure S17) is comparable to that obtained from MTT assay (0.16 μM). Consistent with the results on HeLa cells, our best derivative 4 turned out to be 14-and 13-times more potent as compared to cisplatin on HT29 colon (IC 50 = 0.38 μM for 4 and 5.5 μM for cisplatin) and SKOV3 ovarian (IC 50 = 0.56 μM for 4 and 7.4 μM for cisplatin) cancer cells, which are poorly sensitive to Pt drugs (Table S1, Figure S18 for dose-response plots).…”

Novel Re(I) Complexes as Potential Selective Theranostic Agents in Cancer Cells and In Vivo in Caenorhabditis elegans Tumoral Strains

“…Aquation of monodentate chloride ligand is a common behavior for metallodrugs and is usually considered an activation step, 64 and some interesting aqua Re(I) carbonyl complexes with high cytotoxicity have been recently reported. 24 So, the evolution of the chlorido complex Re1 (1 mM) in methanol- d 4 , containing adventitious water, was monitored by 400 MHz 1 H NMR spectroscopy at 25 °C at different time points (from day 0 to day 3).…”