Iron(III) complexes of a pyridoxal Schiff base for enhanced cellular uptake with selectivity and remarkable photocytotoxicity.

Abstract

Iron(III) complexes of pyridoxal (vitamin B6, VB6) or salicylaldehyde Schiff bases and modified dipicolylamines, namely, [Fe(B)(L)](NO3) (1-5), where B is phenyl-N,N-bis((pyridin-2-yl)methyl)methanamine (phbpa in 1), (anthracen-9-yl)-N,N-bis((pyridin-2-yl)methyl)methanamine (anbpa in 2, 4) and (pyren-1-yl)-N,N-bis((pyridin-2-yl)methyl)methanamine (pybpa in 3, 5) (H2L(1) is 3-hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyridine (1-3) and H2L(2) is 2-[(2-hydroxyphenyl-imino)methyl]phenol), were prepared and their uptake in cancer cells and photocytotoxicity were studied. Complexes 4 and 5, having a non-pyridoxal Schiff base, were prepared to probe the role of the pyridoxal group in tumor targeting and cellular uptake. The PF6 salt (1a) of complex 1 is structurally characterized. The complexes have a distorted six-coordinate FeN4O2 core where the metal is in the +3 oxidation state with five unpaired electrons. The complexes display a ligand to metal charge transfer band near 520 and 420 nm from phenolate to the iron(III) center. The photophysical properties of the complexes are explained from the time dependent density functional theory calculations. The redox active complexes show a quasi-reversible Fe(III)/Fe(II) response near -0.3 V vs saturated calomel electrode. Complexes 2 and 3 exhibit remarkable photocytotoxicity in various cancer cells with IC50 values ranging from 0.4 to 5 μM with 10-fold lower dark toxicity. The cell death proceeded by the apoptotic pathway due to generation of reactive oxygen species upon light exposure. The nonvitamin complexes 4 and 5 display 3-fold lower photocytotoxicity compared to their VB6 analogues, possibly due to preferential and faster uptake of the vitamin complexes in the cancer cells. Complexes 2 and 3 show significant uptake in the endoplasmic reticulum, while complexes 4 and 5 are distributed throughout the cells without any specific localization pattern.

• Authors: Uttara Basu, Ila Pant, Akhtar Hussain, Paturu Kondaiah, Akhil R Chakravarty
• Journal: Inorganic chemistry (Inorg Chem) Vol. 54 Issue 8 Pg. 3748-58 (Apr 20 2015) ISSN: 1520-510X [Electronic] United States
• PMID: 25849848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ferric Compounds
• Photosensitizing Agents
• Reactive Oxygen Species
• Schiff Bases
• Pyridoxal

Topics

• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Ferric Compounds (chemical synthesis, chemistry, metabolism, pharmacology)
• HeLa Cells
• Humans
• Light
• MCF-7 Cells
• Models, Molecular
• Molecular Structure
• Photosensitizing Agents (chemical synthesis, chemistry, metabolism, pharmacology)
• Pyridoxal (chemical synthesis, chemistry, metabolism, pharmacology)
• Quantum Theory
• Reactive Oxygen Species (metabolism)
• Schiff Bases (chemical synthesis, chemistry, metabolism, pharmacology)
• Structure-Activity Relationship