Dual-action Ru(II) polypyridyl complexes containing π-expansive ligands are capable of exhibiting both photochemotherapeutic (PCT) and photodynamic therapeutic (PDT) behavior. Following visible light irradiation, these complexes can treat cancer through the photoinduced release of a drug (PCT) and the production of cytotoxic reactive oxygen species (PDT) due to the existence of energetically accessible 3LF excited states and long-lived 3ππ* excited states. Lipophilicity and the ability to intercalate into DNA are known to affect the cytotoxicity of Ru(II) complexes and modification of these characteristics are known to influence the efficacy of cancer treatment. The prototypical dual-active complex [Ru(tpy)(Me2dppn)(py)]2+ (tpy = 2,2':6',2''-terpyridine; Me2dppn = dimethylbenzo[i]dipyrido[3,2-a:2',3'-c]phenazine; py = pyridine) was synthetically modified to prevent DNA intercalation by addition of substituted phenyl rings. This minor modification was found to increase lipophilicity and reduce cytotoxicity against the prostate cancer cell line DU-145. Data indicated that intercalation was not mandatory for cytotoxicity, yet may increase cell death, and that lipophilicity in these complexes is not directly correlated to toxicity. Additionally, the pyridine ligand, a model for drugs that bind via a similar motif, was substituted with an analog of the CYP3A4 inhibitor ritonavir. Controlled inhibition of CYP3A4, a cytochrome P450 isoform known for drug metabolization in the liver, has been found to be effective in multi-drug therapies for treating HIV and hepatitis C. Dual-active complexes containing the CYP3A4 inhibitor were found to greatly enhance DU-145 cytotoxicity in a multi-drug treatment with the anti-cancer drug vinblastine relative to vinblastine alone. This work provided the first example of in situ synergism between a dual-active Ru(II) complex and an anti-cancer drug for the treatment of cancer cells.

Prostate cancer treatment using dual-active Ru(II) polypyridyl complexes: Roles of DNA intercalation and CYP3A4 inhibition

ACS Spring Meeting 2021

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