The
discovery of new light-triggered prodrugs based on ruthenium
(II) complexes is a promising approach for photoactivated chemotherapy
(PACT). The light-mediated activation of “strained”
Ru(II) polypyridyl complexes resulted in ligand release and produced
a ligand-deficient metal center capable of forming covalent adducts
with biomolecules such as DNA. Based on the strategy of exploiting
structural distortion to activate photochemistry, biologically active
small molecules were coordinated to a Ru(II) scaffold to create light-triggered
dual-action agents. Thirteen new Ru(II) complexes with pyridyl-pyrazol(in)e
ligands were synthesized, and their photochemical reactivity and anticancer
properties were investigated. Isomeric bidentate ligands were investigated,
where “regular” ligands (where the coordinated nitrogens
in the heterocycles are linked by C–C atoms) were compared
to “inverse” isomers (where the coordinated nitrogens
in the heterocycles are linked by C–N atoms). Coordination
of the regular 3-(pyrid-2-yl)-pyrazol(in)es to a Ru(II) bis-dimethylphenanthroline
scaffold yielded photoresponsive compounds with promising photochemical
and biological properties, in contrast to the inverse 1-(pyrid-2-yl)-pyrazolines.
The introduction of a phenyl ring to the 1
N
-pyrazoline
cycle increased the distortion in complexes and improved ligand release
upon light irradiation (470 nm) up to 5-fold in aqueous media. Compounds
1
–
8
, containing pyridyl-pyrazol(in)e ligands,
were at least 20–80-fold more potent than the parent pyridyl-pyrazol(in)es,
and exhibited biological activity in the dark, with half-maximal inhibitory
concentration (IC
50
) values ranging from 0.2 to 7.6 μM
in the HL60 cell line, with complete growth inhibition upon light
irradiation. The diversification of coligands and introduction of
a carboxylic acid into the Ru(II) complex resulted in compounds
9
–
12
, with up to 146-fold improved phototoxicity
indices compared with complexes
1
–
8
.