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.

Novel Cyclometalated Fe(II) Complex with NCN Pincer and BODIPY‐Appended 4'‐Ethynyl‐2,2':6',2”‐terpyridine as Mitochondria‐Targeted Photodynamic Anticancer Agents

“…This observation can be related to increases the lipophilicity by ligand HL, which probably assists in cellular uptake of the complex (Table ). An average cell contained 16.31 ± 0.4 fmol of iron for complex 1 without ligand HL, which is comparable to those reported in the cellular uptake studies of other iron complexes …”

“…An average cell contained 16.31 ± 0.4 fmol of iron for complex 1 without ligand HL, which is comparable to those reported in the cellular uptake studies of other iron complexes. [22,55] Cellular localization of complex 1 in HeLa cells was investigated by confocal microscopy with Mito-Tracker green, which is a widely used commercially available mitochondrial dye (Figure 2). Confocal microscopic observation shows that complex 1 can effectively penetrate into HeLa cells after 2 h incubation, as indicated by the intense and punctate red fluorescence in the cytoplasm (Figure 2).…”

Synthesis and structural characterization of N-(2-{[(2E)-2-(2-hydroxybenzylidene)- hydrazinyl] carbonyl}-phenyl)benzamide (HL) and its Co(II), Fe(III), Cu(II) and Zn(II) complexes. X-ray crystal structure of HL

“…It can be proposed a tetrahedral geometry for the Cu(II) and Zn(II) complexes; distorted octahedral and square pyramidal geometries for the Fe(III) and Co(II) complexes, respectively [43][44][45][46][47]. In addition, the ball-stick structure for the Cu(II) and Zn(II) complexes is shown in Figure 8.…”

Enhancement of Antiangiogenic Efficacy of Iron(II) Complex by Selenium Substitution

“…Studies also demonstrated promising photocytotoxic properties of iron complexes in cancer treatments. Basu et al . recently discovered that the introduction of a pyridoxal Schiff base enhanced the cellular uptake of iron(III) complexes and resulted in remarkable photocytotoxicity.…”