Ir(III) Compounds Containing a Terdentate Ligand Are Potent Inhibitors of Proliferation and Effective Antimetastatic Agents in Aggressive Triple-Negative Breast Cancer Cells

Abstract

Herein, we report a series of new octahedral iridium(III) complexes Ir1−Ir9 of the type [Ir(N^N^N)(C^N)Cl]PF 6 (N^N^N = 4′-(p-tolyl)-2,2′:6′,2″-terpyridine; C^N = deprotonated 2-arylbenzimidazole backbone) to introduce new metal-based compounds for effective inhibition of metastatic processes in triple-negative breast cancer (TNBC).The results show that the structural modifications within the C^N scaffold strongly impact the antimetastatic properties of these complexes in TNBC cells. Furthermore, testing the antimetastatic effects of the investigated Ir complexes revealed that the highest antimetastatic activity in TNBC cells is exhibited by complex Ir1. This result was in contrast to the effects of the clinically used drug doxorubicin used in conventional chemotherapy of TNBC, which conversely promoted metastatic properties of TNBC cells. Thus, the latter result suggests that doxorubicin chemotherapy may increase the risk of metastasis of breast cancer cells, so the search for new drugs to treat breast cancer that would show better antitumor effects than doxorubicin is justified.

Photoactivatable Ruthenium Complexes Containing Minimal Straining Benzothiazolyl-1,2,3-triazole Chelators for Cancer Treatment

“…53−57 The 1 IL fluorescent emission observed at 362 nm in ACN for complexes Ru1 and Ru2 was more intense than that observed for complex Ru3. All the complexes present weak yellow phosphorescence from 3 MLCT states at room temperature in ACN solutions, see Table 3. The emission from 3 MLCT varies little from one compound to another, which could be indicate of the π* acceptor orbital of 3 MLCT is similar in each complex.…”

“…In all complexes, the T 1 state mainly originates from HOMO → LUMO (70%) transition (Table S6) and characterized as 3 MLCT. The other high energy emission band are derived from triplet states which are predominantly ligand centered 3 LLCT/ 3 ILCT. Finally, it is interesting to note that the S 0 −T 1 transition is accompanied by a change in the dipole moment (Table S8), which is greater for Ru5 and Ru1, in particular in water and Ru4 exhibited the lowest change in the dipolar moment in the S 0 −T 1 transition.…”

“…Except for complex Ru4, these complexes exhibit similar efficient photosubstitution than other complexes with bidentate ligands and steric hindrance which have t 1/2 < 5 min. In these photolabile compounds the 3 MLCT excited states generated photochemically are quenched by low lying metal-centered ( 3 MC) triplet excited states that lead to nonradiative decay and photosubstitution. 59,60 As stated above, the release of the BTAT ligand from the corresponding prodrug Ru1−Ru5 could be confirmed by HPLC using ACN solutions of the complexes at time zero and after 1 h of irradiation with blue light (λ ex = 465 nm, 4 mW/ cm 2 ) (Figures S47−S51).…”

“…Different therapeutic approaches can be selected depending on their aggressiveness, stage, and accessibility, but in general terms, the standard strategy for malignant tumors usually involves resection of the tumor tissue, followed by localized radiotherapy and immunotherapy or chemotherapy. Systemic chemotherapy exhibits considerable limitations related to its typically low selectivity, which leads to numerous undesirable side effects, and drug resistances, relapses and metastatic tumors. , Metal-based therapeutics, with their diverse coordination structures, and high tunability, possess unique properties, when compared to organic compounds. − The use of the stimulus-responsive “prodrug approach” is very appealing to reduce the systemic toxicity, , and in recent years, the photochemical and photophysical properties of precious metal complexes, such as strong spin–orbit coupling (SOC) effects, and tunable excited-state electronic configurations, have been exploited to make light-activated drugs for use as photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) agents that allow to minimize effects on normal tissue through the use of light directed to the tumor, achieving a high temporal and spatial control. − PDT requires the combination of three fundamental components, namely, a nontoxic photosensitizer (PS), ground state molecular oxygen ( 3 O 2 ), and light, to generate highly toxic singlet oxygen ( 1 O 2 ) in a photocatalytic manner and subsequently to induce cancer eradication with low systemic toxicity . Thus, it is important to highlight that the polypyridyl Ru­(II) complex TLD-1433, reported by McFarland and co-workers, is being currently studied as a photosensitizer for PDT in Phase II clinical trials for the treatment of nonmuscle invasive bladder cancer (NMIBC).…”

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

“…In general, the mechanisms of action of Re(I) anticancer complexes containing the fac -[Re(CO) 3 ] + core are quite distinct from that of conventional platinum agents, ,− that is dependent on covalent bond formation to DNA . Targeting vulnerable organelles, such as the mitochondria, is one strategy that has been employed to combat resistance to chemotherapeutics, and that generally is the case for rhenium(I) tricarbonyl complexes. ,− However, their in vivo antitumor efficacy is still little known. , Our previous results on ruthenium(II) and iridium(III) organometallic complexes of the types [Ru(C^N)(N^N) 2 ] + , [Ir(C^N) 2 (N^N)] + , and [Ir(C^N)(N^N^N)] + demonstrated that slight modifications on the benzimidazole-based ligand core rendered high anticancer activities in vitro , − the N-substituted butyl group serving to adjust the lipophilic properties and enhance cellular uptake and targeting preferentially mitochondria, , whereas the ester group attached to the benzimidazole backbone could act as a handle for further functionalization …”