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Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy.

ABSTRACT: One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of ¹O₂. We have obtained derivatives of formulas [Cp*Ir(C^∧N)Cl] and [Cp*Ir(C^∧N)L]BF₄ with different degrees of π-expansion in the C^∧N ligands. Complexes with the more π-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Time-dependent density functional theory (TD-DFT) calculations nicely explain the effect of the π-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of half-sandwich iridium cyclometalated complexes active in PDT.

SUBMITTER: Gonzalo-Navarro C

PROVIDER: S-EPMC10859961 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy.

Gonzalo-Navarro Carlos C Zafon Elisenda E Organero Juan Angel JA Jalón Félix A FA Lima Joao Carlos JC Espino Gustavo G Rodríguez Ana María AM Santos Lucía L Moro Artur J AJ Barrabés Sílvia S Castro Jessica J Camacho-Aguayo Javier J Massaguer Anna A Manzano Blanca R BR Durá Gema G

Journal of medicinal chemistry 20240130 3

One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of 1O2. We have obtained derivatives of formulas [Cp*Ir(C∧N)Cl] and [Cp*Ir(C∧N)L]BF4 with different degree ...[more]

PMID: 38291666

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Project description:We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(η5-Cp*)Ir(2-(R'-phenyl)-R-pyridine)Cl] bearing either an electron-donating (-OH, -CH2OH, -CH3) or electron-withdrawing (-F, -CHO, -NO2) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(η5-Cp*)Ir(2-(2'-fluorophenyl)pyridine)Cl] (1) and [(η5-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) exhibit the expected "piano-stool" configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD+. Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC50 values ranging from 1 to 89 μM, with the most potent complex, [(η5-Cp*)Ir(2-(2'-methylphenyl)pyridine)Cl] (13) (A2780 IC50 = 1.18 μM), being 10× more active than the parent, [(η5-Cp*)Ir(2-phenylpyridine)Cl], and 2× more active than [(η5-CpxPh)Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(η5-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) and [(η5-Cp*)Ir(2-phenyl-5-fluoropyridine)Cl] (4) preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems.

Dataset Information

Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy.

Publications

Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy.

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