Structure-activity relationships of novel iron chelators for the treatment of iron overload disease: the methyl pyrazinylketone isonicotinoyl hydrazone series.
The design of novel Fe chelators with high Fe mobilization efficacy and low toxicity remains an important priority for the treatment of Fe overload disease. We have designed and synthesized the novel methyl pyrazinylketone isonicotinoyl hydrazone (HMPIH) analogs based on previously investigated aroylhydrazone chelators. The HMPIH series demonstrated high Fe mobilization efficacy from cells and showed limited to moderate antiproliferative activity. Importantly, this novel series demonstrated irreversible electrochemistry, which was attributed to the electron-withdrawing effects of the noncoordinating pyrazine N-atom. The latter functionality played a major role in forming redox-inactive complexes that prevent reactive oxygen species generation. In fact, the Fe complexes of the HMPIH series prevented the oxidation of ascorbate and hydroxylation of benzoate. We determined that the incorporation of electron-withdrawing groups is an important feature in the design of N, N, O-aroylhydrazones as candidate drugs for the treatment of Fe overload disease.
Kalinowski
Danuta S
DS
Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
Sharpe
Philip C
PC
Bernhardt
Paul V
PV
Richardson
Des R
DR
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001205:Ascorbic Acid / Q000378:metabolism; D001565:Benzoates / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006900:Hydroxylation; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019190:Iron Overload / Q000188:drug therapy*; D007504:Iron Radioisotopes; D007539:Isonicotinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D010084:Oxidation-Reduction; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001565:Benzoates; D006835:Hydrazones; D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D007539:Isonicotinic Acids; D007659:Ketones; D008024:Ligands; D011719:Pyrazines; C528050:methyl pyrazinylketone 4-aminobenzoyl hydrazone; C528049:methyl pyrazinylketone 4-hydroxybenzoyl hydrazone; D007501:Iron; D001205:Ascorbic Acid