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Novel 3,6-bis(imidazolidine)acridines as effective photosensitizers for photodynamic therapy.

Abstract：

:The photoeffect of new proflavine derivatives with DNA-binding and antitumour activities, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides (AcrDIMs), was studied to evaluate them as potential photosensitizers for photodynamic antitumor therapy. EPR measurements showed that superoxide radical anion and singlet oxygen were produced upon irradiation of AcrDIMs with UV-A light (>300nm) in the presence of molecular oxygen. This indicates that AcrDIMs may act as photosensitizers. The most active pentyl-AcrDIM and hexyl-AcrDIM displayed photocytotoxic effect toward the mouse lymphocytic leukemia cell line L1210 and human ovarian cancer cells A2780. Antitumor activity of pentyl-AcrDIM increased as high as about 12 times (72h incubation) after irradiation of A2780 cells (365nm, 1.05J/cm(2)). The photocytotoxicity seems to be associated with oxidative stress. Concerning the cell cycle, flow cytometry showed an arrest in the S-phase already 4h after irradiation. In a comet assay, no genotoxicity of AcrDIMs was found. Typical morphologic changes and formation of DNA-ladders indicated induction of apoptotic cell death, though no activation of caspase-3 was observed. Investigation of intracellular localization of pentyl-AcrDIM confirmed its partial accumulation in mitochondria and lysosomes. After irradiation of the A2780 cells, colocalization of pentyl-AcrDIM with monodansylcadaverine, a lysosomal dye, was proven, suggesting that lysosomes in the irradiated cells may be involved in the cell death.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Cižeková L,Grolmusová A,Ipóthová Z,Barbieriková Z,Brezová V,Hunáková L,Imrich J,Janovec L,Dovinová I,Paulíková H

doi

10.1016/j.bmc.2014.07.013

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

4684-93

issue

17

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(14)00517-3

journal_volume

22

pub_type

杂志文章

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