An iron complex of dipyridophenazine as a potent photocytotoxic agent in visible light.
Ternary iron(III) complexes [FeL(B)] (1-3) of a trianionic tetradentate phenolate-based ligand (L) and phenanthroline base (B), namely, 1,10-phenanthroline (phen, 1), dipyridoquinoxaline (dpq, 2), and dipyridophenazine (dppz, 3), have been prepared and structurally characterized and their DNA binding, cleavage, and photocytotoxic properties studied. The complexes with a FeN(3)O(3) core show the Fe(III)/Fe(II) redox couple near -0.6 V in DMF, a magnetic moment value of approximately 5.9 micro(B), and a binding propensity to both calf thymus DNA and bovine serum albumin (BSA) protein. They exhibit red-light-induced DNA cleavage activity following a metal-assisted photoredox pathway forming HO(*) radicals but do not show any photocleavage of BSA in UV-A light. Complex 3 displays photocytotoxicity in the human cervical cancer cell line (HeLa) and human keratinocyte cell line (HaCaT) with respective IC(50) values of 3.59 microM and 6.07 microM in visible light and 251 nM and 751 nM in UV-A light of 365 nm. No significant cytotoxicity is observed in the dark. The photoexposed HeLa cells, treated prior with complex 3, have shown marked changes in nuclear morphology as demonstrated by Hoechst 33258 nuclear stain. Generation of reactive oxygen species has been evidenced from the fluorescence enhancement of dichlorofluorescein upon treatment with 3 followed by photoexposure. Nuclear chromatin cleavage has been observed in acridine orange/ethidium bromide dual staining of treated HeLa cells and from alkaline single-cell gel electrophoresis. Caspase 3/7 activity in HeLa cells has been found to be upregulated by only 4 fold after photoirradiation, signifying the fact that cell death through a caspase 3/7 dependent pathway may not be solely operative.
Saha
Sounik
S
Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India.
Majumdar
Ritankar
R
Roy
Mithun
M
Dighe
Rajan R
RR
Chakravarty
Akhil R
AR
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008027:Light; D010618:Phenanthrolines / Q000737:chemistry / Q000494:pharmacology; D010619:Phenazines / Q000737:chemistry / Q000494:pharmacology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000494:pharmacology*; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D003603:Cytotoxins; D005290:Ferric Compounds; D010618:Phenanthrolines; D010619:Phenazines; D017319:Photosensitizing Agents; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D012710:Serum Albumin, Bovine; D004247:DNA; C427203:calf thymus DNA; D020169:Caspases; C025205:1,10-phenanthroline