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Structure-activity relationships of novel salicylaldehyde isonicotinoyl hydrazone (SIH) analogs: iron chelation, anti-oxidant and cytotoxic properties.

Potůčková E, Hrušková K, Bureš J, Kovaříková P, Špirková IA, Pravdíková K, Kolbabová L, Hergeselová T, Hašková P, Jansová H, Macháček M, Jirkovská A, Richardson V, Lane DJ, Kalinowski DS, Richardson DR, Vávrová K, Šimůnek T - PLoS ONE (2014)

Bottom Line: The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity.A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects.Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

View Article: PubMed Central - PubMed

Affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.

ABSTRACT
Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

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Stabilities of SIH and its novel analogs in rabbit plasma.SIH (A), redSIH (B), redHAPI (C), redHPPI (D), BHAPI (E), BHPPI (F), 2API (G), 7HII (H), H16 (I), H17 (J), H18 (K) and H28 (L) were incubated at 37°C in rabbit plasma and their concentrations were analyzed using HPLC every 60 min until t = 600 min. Results are expressed as a percentage of the concentration at t = 0 min (100 µM). Results are Mean ±SD (n = 3 experiments). Statistical significance (ANOVA): * p<0.05, ** p<0.01, *** p<0.001 compared to the concentration at t = 0 min (100%).
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pone-0112059-g002: Stabilities of SIH and its novel analogs in rabbit plasma.SIH (A), redSIH (B), redHAPI (C), redHPPI (D), BHAPI (E), BHPPI (F), 2API (G), 7HII (H), H16 (I), H17 (J), H18 (K) and H28 (L) were incubated at 37°C in rabbit plasma and their concentrations were analyzed using HPLC every 60 min until t = 600 min. Results are expressed as a percentage of the concentration at t = 0 min (100 µM). Results are Mean ±SD (n = 3 experiments). Statistical significance (ANOVA): * p<0.05, ** p<0.01, *** p<0.001 compared to the concentration at t = 0 min (100%).

Mentions: The stabilities of the newly prepared chelators in rabbit plasma were studied using HPLC analysis following a 600 min (10 h) incubation in vitro. The results were expressed as a percentage of the initial concentration of chelators at time t = 0 min. In our previous studies, SIH showed low stability, with less than 10% of SIH remaining intact after 180 min [33] and this was confirmed in our present investigation (Fig. 2A). The methylated and ethylated analogs of SIH, namely HAPI and HPPI, were markedly more resistant than SIH to hydrolysis in plasma. In fact, HAPI and HPPI were present at 26% and 41% of their original concentration at t = 600 min [33].


Structure-activity relationships of novel salicylaldehyde isonicotinoyl hydrazone (SIH) analogs: iron chelation, anti-oxidant and cytotoxic properties.

Potůčková E, Hrušková K, Bureš J, Kovaříková P, Špirková IA, Pravdíková K, Kolbabová L, Hergeselová T, Hašková P, Jansová H, Macháček M, Jirkovská A, Richardson V, Lane DJ, Kalinowski DS, Richardson DR, Vávrová K, Šimůnek T - PLoS ONE (2014)

Stabilities of SIH and its novel analogs in rabbit plasma.SIH (A), redSIH (B), redHAPI (C), redHPPI (D), BHAPI (E), BHPPI (F), 2API (G), 7HII (H), H16 (I), H17 (J), H18 (K) and H28 (L) were incubated at 37°C in rabbit plasma and their concentrations were analyzed using HPLC every 60 min until t = 600 min. Results are expressed as a percentage of the concentration at t = 0 min (100 µM). Results are Mean ±SD (n = 3 experiments). Statistical significance (ANOVA): * p<0.05, ** p<0.01, *** p<0.001 compared to the concentration at t = 0 min (100%).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231169&req=5

pone-0112059-g002: Stabilities of SIH and its novel analogs in rabbit plasma.SIH (A), redSIH (B), redHAPI (C), redHPPI (D), BHAPI (E), BHPPI (F), 2API (G), 7HII (H), H16 (I), H17 (J), H18 (K) and H28 (L) were incubated at 37°C in rabbit plasma and their concentrations were analyzed using HPLC every 60 min until t = 600 min. Results are expressed as a percentage of the concentration at t = 0 min (100 µM). Results are Mean ±SD (n = 3 experiments). Statistical significance (ANOVA): * p<0.05, ** p<0.01, *** p<0.001 compared to the concentration at t = 0 min (100%).
Mentions: The stabilities of the newly prepared chelators in rabbit plasma were studied using HPLC analysis following a 600 min (10 h) incubation in vitro. The results were expressed as a percentage of the initial concentration of chelators at time t = 0 min. In our previous studies, SIH showed low stability, with less than 10% of SIH remaining intact after 180 min [33] and this was confirmed in our present investigation (Fig. 2A). The methylated and ethylated analogs of SIH, namely HAPI and HPPI, were markedly more resistant than SIH to hydrolysis in plasma. In fact, HAPI and HPPI were present at 26% and 41% of their original concentration at t = 600 min [33].

Bottom Line: The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity.A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects.Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

View Article: PubMed Central - PubMed

Affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.

ABSTRACT
Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

Show MeSH
Related in: MedlinePlus