Catch and Release Photosensitizers: Combining Dual-Action Ruthenium Complexes with Protease Inactivation for Targeting Invasive Cancers.
J Am Chem Soc
; 140(43): 14367-14380, 2018 10 31.
Article
em En
| MEDLINE
| ID: mdl-30278123
ABSTRACT
Dual action agents containing a cysteine protease inhibitor and Ru-based photosensitizer for photodynamic therapy (PDT) were designed, synthesized, and validated in 2D culture and 3D functional imaging assays of triple-negative human breast cancer (TNBC). These combination agents deliver and release Ru-based PDT agents to tumor cells and cause cancer cell death upon irradiation with visible light, while at the same time inactivating cathespin B (CTSB), a cysteine protease strongly associated with invasive and metastatic behavior. In total five Ru-based complexes were synthesized with the formula [Ru(bpy)2(1)](O2CCF3)2 (3), where bpy = 2,2'-bipyridine and 1 = a bipyridine-based epoxysuccinyl inhibitor; [Ru(tpy)(NN)(2)](PF6)2, where tpy = terpiridine, 2 = a pyridine-based epoxysuccinyl inhibitor and NN = 2,2'-bipyridine (4); 6,6'-dimethyl-2,2'-bipyridine (5); benzo[ i]dipyrido[3,2- a2',3'- c]phenazine (6); and 3,6-dimethylbenzo[ i]dipyrido[3,2- a2',3'- c]phenazine (7). Compound 3 contains a [Ru(bpy)3]2+ fluorophore and was designed to track the subcellular localization of the conjugates, whereas compounds 4-7 were designed to undergo either photoactivated ligand dissociation and/or singlet oxygen generation. Photochemical studies confirmed that complexes 5 and 7 undergo photoactivated ligand dissociation, whereas 6 and 7 generate singlet oxygen. Inhibitors 1-7 all potently and irreversibly inhibit CTSB. Compounds 4-7 were evaluated against MDA-MB-231 TNBC and MCF-10A breast epithelial cells in 2D and 3D culture for effects on proteolysis and cell viability under dark and light conditions. Collectively, these data reveal that 4-7 potently inhibit dye-quenched (DQ) collagen degradation, whereas only compound 7 causes efficient cell death under light conditions, consistent with its ability to release a Ru(II)-based photosensitizer and to also generate 1O2.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeo Hidrolases
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Inibidores de Proteases
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Rutênio
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Fármacos Fotossensibilizantes
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Complexos de Coordenação
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos