Structure-activity relationships of novel salicylaldehyde isonicotinoyl hydrazone (SIH) analogs: iron chelation, anti-oxidant and cytotoxic properties.
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.
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Eliška
E
Potůčková
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Kateřina
K
Hrušková
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Jan
J
Bureš
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Petra
P
Kovaříková
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Iva A
IA
Špirková
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Kateřina
K
Pravdíková
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Lucie
L
Kolbabová
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Tereza
T
Hergeselová
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Pavlína
P
Hašková
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Hana
H
Jansová
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Miloslav
M
Macháček
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Anna
A
Jirkovská
Molecular Pharmacology and Pathology Program, Bosch Institute and Department of Pathology, University of Sydney, Sydney, Australia.
Vera
V
Richardson
Molecular Pharmacology and Pathology Program, Bosch Institute and Department of Pathology, University of Sydney, Sydney, Australia.
Darius J R
DJ
Lane
Molecular Pharmacology and Pathology Program, Bosch Institute and Department of Pathology, University of Sydney, Sydney, Australia.
Danuta S
DS
Kalinowski
Molecular Pharmacology and Pathology Program, Bosch Institute and Department of Pathology, University of Sydney, Sydney, Australia.
Des R
DR
Richardson
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Kateřina
K
Vávrová
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
Tomáš
T
Šimůnek
D000447:Aldehydes / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006861:Hydrogen Peroxide / Q000633:toxicity; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D032446:Myoblasts / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D013329:Structure-Activity Relationship
D000447:Aldehydes; D000970:Antineoplastic Agents; D000975:Antioxidants; D006835:Hydrazones; D007502:Iron Chelating Agents; C413684:salicylaldehyde isonicotinoyl hydrazone; D006861:Hydrogen Peroxide