Much effort over the past five decades has been devoted to the design and synthesis of metal-based anticancer agents. Metal-based antitumor agents can target DNA by forming covalent lesions or by intercalating into the double helix of DNA. Current therapies have limitations stemming from the lack of specificity and systemic toxicity. Our group has shown that Rh2(µ-O2CCH3)4 and other derivatives containing electron accepting ligands can bind in vitro to nucleotides, form intra-strand DNA cross-links and interact with other biologically relevant molecules. As part of our interest in metal anticancer agents, we have targeted a series of dirhodium(II,II) complexes with different types of bridging and chelating ligands in the same molecule, work that led to the isolation of families of such compounds that are inactive towards cancer cells in the dark but which are toxic upon irradiation has been synthesized and characterized. Formamidinate compounds of the type [Rh2(F4form)(µ-O2CCH3)(N-N)2][OAc]2with electron accepting chelating ligands (N-N) (N-N = dpq (dipyrido[3,2-f:2',3'-h]-quinoxaline), dppz (dipyrido[3,2-a:2’,3’-c]phenazine) and dppn (benzodipyrido[3,2-a:2’,3’-h]quinoxaline)) were studied as well as the partial paddlewheels [Rh2(2-pyrrolidinato)4(CH3CN)2],[Rh2(2-pyrrolidinato)3(CH3CN)6]2+ and (7) [Rh2(2-pyrrolidinato)2(η1-pyrrolidinato)(CH3CN)5]2+ [Rh2(F4form)(µ-O2CCH3)(CH3CN)6]2+(8) and [Rh2(PC6H4Ph2)(µ-O2CCH3)(CH3CN)6]2+. The cytostatic effect of these compounds were tested against cervical and ovarian cancer cells in the dark and also upon irradiation. Fluorescence probes were used to elucidate possible cell death mechanisms of action. NIC/ADR-Res cells were incubated with the compounds for 2 h in the dark and then irradiated for 1 h. The compound ([Rh2(F4form)(µ-O2CCH3)(dppn)2][OAc]2) is the most effective at inhibiting cell growth with an LC50 value of 336 ± 55 µM in the dark and 19 ± 4 µM upon irradiation. The results of a JC-1 assay indicate that several of the compounds induce changes in the mitochondrial membrane potential as early as 2 h as observed from a time lapse experiment. Annexin V binding studies indicate that t some of the compounds induces cell death through mitochondrial mediated pathways.

Biological studies of dirhodium(II,II) based compounds and their applications as photochemotherapeutic agents

249th National Meeting (2015)

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