Exploring the Effect of Polypyridyl Ligands on the Anticancer Activity of Phosphorescent Iridium(III) Complexes: From Proteosynthesis Inhibitors to Photodynamic Therapy Agents

Abstract

A series of five kinetically inert bis-cyclometalated Ir complexes of general formula [Ir(C^N) (N^N)][PF ] [C^N=2-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-benzo[d]imidazol-κN,C; N^N=1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3), benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn, 4), and dipyrido[3,2-a:2',3'-c]phenazine-10,11-imidazolone (dppz-izdo, 5)] were designed and synthesized to explore the effect of the degree of π conjugation of the polypyridyl ligand on their toxicity in cancer cells. We show that less-lipophilic complexes 1 and 2 exhibit the highest toxicity [sub-micromolar inhibitory concentration (IC ) values] in A2780, HeLa, and MCF-7 cancer cells, and they are markedly more efficient than clinically used platinum drugs. It is noteworthy that the investigated Ir agents display the capability to overcome acquired and inherent resistance to conventional cisplatin (in A2780cisR and MCF-7 cells, respectively). We demonstrate that the Ir complexes, unlike clinically used platinum antitumor drugs, do not kill cells through DNA-damage response. Rather, they kill cells by inhibiting protein translation by targeting preferentially the endoplasmic reticulum. Our findings also reveal that the toxic effect of the Ir complexes can be significantly potentiated by irradiation with visible light (by more than two orders of magnitude). The photopotentiation of the investigated Ir complexes can be attributed to a marked increase (≈10-30-fold) in intracellular reactive oxygen species. Collectively, these data highlight the functional diversity of antitumor metal-based drugs and the usefulness of a mechanism-based rationale for selecting candidate agents that are effective against chemoresistant tumors for further preclinical testing.

A Rhenium Isonitrile Complex Induces Unfolded Protein Response‐Mediated Apoptosis in Cancer Cells

“…Thus, the development of new chemotherapeutic agents that target the ER is a promising strategy for the treatment of cancer . Recently, several transition‐metal complexes bearing polypyridyl ligands have been discovered to induce anticancer activity through ER stress and the UPR, suggesting that the exploration of these nontraditional scaffolds may give rise to promising drug candidates . In this context, our group has been exploring the anticancer activity of polypyridyl rhenium(I) tricarbonyl complexes .…”

“…[5] Recently, several transition-metal complexes bearing polypyridyl ligands have been discoveredt oi nduce anticancer activity throughE R stress and the UPR, suggesting that the explorationo ft hese nontraditionals caffoldsm ay give rise to promising drug candidates. [6][7][8][9][10][11] In this context,our group has been exploringthe anticancera ctivity of polypyridyl rhenium(I) tricarbonyl complexes. [12][13][14][15] Certain members of this class of compounds exhibit potent cytotoxic activity,w hich can be leveragedf or their use as anticancer agents.…”

Towards Novel Photodynamic Anticancer Agents Generating Superoxide Anion Radicals: A Cyclometalated IrIIIComplex Conjugated to a Far‐Red Emitting Coumarin

“…Thephotophysical properties of conjugate 6 were studied in four solvents of different polarity and compared with those of coumarin 2 and Ir III complex 3 ( Figure 1a nd Supporting Information, Table S1 and and Figures S3-S9). Them ost relevant findings are that the Ir III complex showed strong red phosphorescence (660 nm), [12] whose intensity decreased in the conjugate in asolvent-dependent manner,indicating that competitive excited-state processes take place.Regarding the coumarin, it showed strong fluorescence (599-609 nm), whose intensity and lifetime decreased strongly in the conjugate, again indicating the existence of competitive excited-state processes.F luorescence of the coumarin could also be observed when the Ir III complex was selectively photoexcited in the conjugate,i ndicating fast energy transfer from the Ir III complex to the coumarin moiety.I nt he presence of oxygen, the Ir III complex produced 1 O 2 in all organic solvents but not in phosphate-buffered saline (PBS). Thec oumarin was am uch worse PS in all solvents;h owever, its 1 O 2 quantum yield increased by one order of magnitude in the conjugate, indicating an enhanced intersystem crossing induced by the heavy Ir III ion, which is consistent with the shortening of its fluorescence lifetime.N evertheless,n og eneration could be detected in PBS.V ery similar quantum yields were observed when either the Ir III complex or the coumarin moiety were selectively photoexcited in organic solvents in conjugate 6, indicating almost 100 %efficient singlet-singlet energy transfer from the Ir III complex to the coumarin.…”

Dipyrrinato‐Iridium(III) Complexes for Application in Photodynamic Therapy and Antimicrobial Photodynamic Inactivation

“…A high phototoxic activity against cells has also been reported for some other types of (2‐phenylpyridyl)iridium(III) complexes [18d, 61] . No significant phototoxic activity was observed for the unfunctionalized complex 52 and the 3‐nitrophenyl‐substituted complexes 61 , 53 , and 66 , the other complexes exhibited a limited phototoxicity in some cell lines.…”