Prooxidant and antioxidant properties of salicylaldehyde isonicotinoyl hydrazone iron chelators in HepG2 cells

Abstract

Background Salicylaldehyde isonicotinoyl hydrazone (SIH) is an iron chelator of the aroylhydrazone class that displays antioxidant or prooxidant effects in different mammalian cell lines. Because the liver is the major site of iron storage, elucidating the effect of SIH on hepatic oxidative metabolism is critical for designing effective hepatic antioxidant therapies. Methods Hepatocyte-like HepG2 cells were exposed to SIH or to analogs showing greater stability, such as N′-[1-(2-Hydroxyphenyl)ethyliden]isonicotinoyl hydrazide (HAPI), or devoid of iron chelating properties, such as benzaldehyde isonicotinoyl hydrazone (BIH), and toxicity, oxidative stress and antioxidant (glutathione) metabolism were evaluated. Results Autoxidation of Fe2+ in vitro increased in the presence of SIH or HAPI (but not BIH), an effect partially blocked by Fe2+ chelation. Incubation of HepG2 cells with SIH or HAPI (but not BIH) was non-toxic and increased reactive oxygen species (ROS) levels, activated the transcription factor Nrf2, induced the catalytic subunit of γ-glutamate cysteine ligase (Gclc), and increased glutathione concentration. Fe2+ chelation decreased ROS and inhibited Nrf2 activation, and Nrf2 knock-down inhibited the induction of Gclc in the presence of HAPI. Inhibition of γ-glutamate cysteine ligase enzymatic activity inhibited the increase in glutathione caused by HAPI, and increased oxidative stress. Conclusions SIH iron chelators display both prooxidant (increasing the autoxidation rate of Fe2+) and antioxidant (activating Nrf2 signaling) effects. General significance Activation by SIH iron chelators of a hormetic antioxidant response contributes to its antioxidant properties and modulates the anti- and pro-oxidant balance.

Preparation, characterization and Microbicide activities of N'-((3-(hydroxyimino)butan-2-ylidene)-2-(phenylamino)acetohydrazide and its complexes

“…This mode of bonding is further supported by the new bands observed in the 638-575, 581-497 and 456-504 ranges related to (MO), two (MN)respectively [55]. The spectra of the bimetallic complexes (4), (8)(9) and (13)(14) suggested the chelation of the ligand in a dibasic tetradentate fashion bonding two metal ions by the three nitrogen atoms of amino, imine and oxima to groups and the enolic oxygen atom, which is supported by i) complete disappearance of the band of both hydroxyl of the oxime as well as the carbonyl group of the acetohydrazide moiety. ii) a negative shift in the position of the NH bands iii) the appearance of an additional band in the range 1500-1527assigned to the emerging of a new C=N group.…”

“…We have not managed to grow diffractable single crystals till now. Complexes (2), (3), (5-7) and (10) and (12) were found to be formed in 1L:1M molar ratio, complexes (4), (8), (9) (13)and (14) were found to adopt M 2 L formulae while complex (11) adopted ML2 configuration. …”

“…The lower magnetic moment of complex (9) than the expected values reported for square planar copper complexes is related to spin-spin interactions between the copper ions [69]. The electronic spectrum of copper complex (8) revealed the presence of two bands at 400 and 580 nm assignable to 2 B 1g → 2 A 1g and 2 B 1g → 2 B 1g transitions. While the magnetic moment of this complex recorded 0.98 BM which is lower than that reported for octahedral copper complexes, this is could be assigned to spin-spin interaction of copper(II) ions in an octahedral environment, support the bimetal nuclear nature of the complex [69].…”

“…Hydrazone ligands represent a class of Schiff base with an extra function group characterized by a nitrogen-nitrogen covalent bond that enhances their capability to form more stable metal complexes via reaction with most of the transition metal ions [6,7]. Both hydrazide and hydrazone compounds have drawn much concern in order to investigate their structures as well as their enormous biomedical activities as: antioxidant [8,9], analgesic, anti-inflammatory [10], antimalarial, anti-leishmanial and anti-trypanosomal [11], anti-convulsant [(12)], antibacterial [13,14], antiplatelet [15], antitumor [16] and antiviral [17,18] activities. The presence of active azomethine NHN=CH-protons in these compounds imparts them a major importance as good candidates for the development of new drugs [19][20][21].…”

“…Complexes (4), (8), (9), (13) and (14) were found to afford M 2 L formulae while complex (11) adopted ML 2 formulae. The ligand acted as a neutral (bidentate [11], tridentate [6,7], monobasic (tridentate [2,3,5,12]), dibasic (tridentate [10], tetradentate [4,8,9,13,14]) chelating to the metal ions via nitrogen atoms of aceto-amino and azomethine groups, carbonyl oxygen atom in its enolic or ketonic form and/or protonated or deprotonated oximino nitrogen atom, adopting an octahedral, tetrahedral or square planar geometry around metal ions. The antimicrobial activity of the ligand, as well as the metal complexes, was examined using Amphotericin B and Amoxicillin as drugstandards against Aspergillus niger (A.niger) and Escherichia coli (E. coli) ,respectively.…”