Carbohydrate-Appended Tumor Targeting Iron(III) Complexes Showing Photocytotoxicity in Red Light

Abstract

Glucose-appended photocytotoxic iron(III) complexes of a tridentate Schiff base phenolate ligand [Fe(bpyag)(L)](NO3) (1–3), where bpyag is N,N-bis(2-pyridylmethyl)-2-aminoethyl-β-d-glucopyranoside and H2L is 3-(2-hydroxyphenylimino)-1-phenylbutan-1-one (H2phap) in 1, 3-(2-hydroxyphenylimino)-9-anthrylbutan-1-one (H2anap) in 2, and 3-(2-hydroxyphenylimino)-1-pyrenylbutan-1-one (H2pyap) in 3, were synthesized and characterized. The complex [Fe(dpma)(anap)](NO3) (4), having bis-(2-pyridylmethyl)benzylamine (dpma), in which the glucose moiety of bpyag is substituted by a phenyl group, was used as a control, and the complex [Fe(dpma)(anap)](PF6) (4a) was structurally characterized by X-ray crystallography. The structure shows a FeN4O2 core in a distorted octahedral geometry. The high-spin iron(III) complexes with magnetic moment value of ∼5.9 μB showed a low-energy phenolate-to-Fe(III) charge-transfer (CT) absorption band as a shoulder near 500 nm with a tail extending to 700 nm and an irreversible Fe(III)–Fe(II) redox couple near −0.6 V versus saturated calomel electrode. The complexes are avid binders to calf thymus DNA and showed photocleavage of supercoiled pUC19 DNA in red (647 nm) and green (532 nm) light. Complexes 2 and 3 displayed significant photocytotoxicity in red light, with an IC50 value of ∼20 μM in HeLa and HaCaT cells, and no significant toxicity in dark. The cell death is via an apoptotic pathway, by generation of reactive oxygen species. Preferential internalization of the carbohydrate-appended complexes 2 and 3 was evidenced in HeLa cells as compared to the control complex 4. A 5-fold increase in the cellular uptake was observed for the active complexes in HeLa cells. The photophysical properties of the complexes are rationalized from the density functional theory calculations.