Thiosemicarbazones from the Old to New: Iron Chelators That Are More Than Just Ribonucleotide Reductase Inhibitors

Yu, Yu; Kalinowski, Danuta S.; Kovačević, Žaklina; Siafakas, A. Rosemary; Jansson, Patric J.; Stefani, Christian; Lovejoy, David B.; Sharpe, Philip C.; Bernhardt, Paul V.; Richardson, Des R.

doi:10.1021/jm900552r

Cited by 359 publications

(330 citation statements)

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“…Recent studies demonstrated that 3-AP led to metHb generation and hypoxia in patients, limiting its usefulness (Yen et al, 2004;Gojo et al, 2007;Knox et al, 2007;Odenike et al, 2008;Traynor et al, 2010). The mechanism responsible was not known and in consideration of the interest in the development of novel thiosemicarbazones as anticancer agents (Yu et al, 2009), it was crucial to investigate their effect on oxyHb, as this would facilitate the development of these compounds (Yu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Methemoglobin Formation by Triapine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and Other Anticancer Thiosemicarbazones: Identification of Novel Thiosemicarbazones and Therapeutics That Prevent This Effect

Quach¹,

Gutierrez²,

Basha³

et al. 2012

Mol Pharmacol

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Thiosemicarbazones are a group of compounds that have received comprehensive investigation as anticancer agents. The antitumor activity of the thiosemicarbazone, 3-amino-2-pyridinecarboxaldehyde thiosemicarbazone (3-AP; triapine), has been extensively assessed in more than 20 phase I and II clinical trials. These studies have demonstrated that 3-AP induces methemoglobin (metHb) formation and hypoxia in patients, limiting its usefulness. Considering this problem, we assessed the mechanism of metHb formation by 3-AP compared with that of more recently developed thiosemicarbazones, including di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT). This was investigated using intact red blood cells (RBCs), RBC lysates, purified oxyhemoglobin, and a mouse model. The chelation of cellular labile iron with the formation of a redox-active thiosemicarbazone-iron complex was found to be crucial for oxyhemoglobin oxidation. This observation was substantiated using a thiosemicarbazone that cannot ligate iron and also by using the chelator, desferrioxamine, that forms a redox-inactive iron complex. Of significance, cellular copper chelation was not important for metHb generation in contrast to its role in preventing tumor cell proliferation. Administration of Dp44mT to mice catalyzed metHb and cardiac metmyoglobin formation. However, ascorbic acid administered together with the drug in vivo significantly decreased metHb levels, providing a potential therapeutic intervention. Moreover, we demonstrated that the structure of the thiosemicarbazone is of importance in terms of metHb generation, because the DpT analog, di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), does not induce metHb generation in vivo. Hence, DpC represents a next-generation thiosemicarbazone that possesses markedly superior properties. This investigation is important for developing more effective thiosemicarbazone treatment regimens.

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Section: Discussionmentioning

confidence: 99%

Methemoglobin Formation by Triapine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and Other Anticancer Thiosemicarbazones: Identification of Novel Thiosemicarbazones and Therapeutics That Prevent This Effect

Quach¹,

Gutierrez²,

Basha³

et al. 2012

Mol Pharmacol

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103

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“…When the mono-N 4 -methylated ligand HAp4mT is used instead, the above mentioned outer-sphere complexation leading to a dead-end complex implies a definite induction period for the formation of the final [Fe(Ap4mT) 2 ] + complex with consequently longer reaction times.…”

Section: Discussionmentioning

confidence: 99%

Biologically active thiosemicarbazone Fe chelators and their reactions with ferrioxamine B and ferric EDTA; a kinetic study

et al. 2012

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The Fe III abstraction from Fe III /DFO and Fe III /EDTA complex systems by thiosemicarbazone ligands derived from 2-acetylpyridine has been studied from a kinetico-mechanistic perspective at relevant pH conditions and at varying temperatures and buffer solutions. The reactions have been found to be extremely dependent on the dominant E/Z isomeric form of the TSC ligands present in the reaction medium. Consequently the isomerisation processes occurring on the free ligands have also been monitored under equivalent conditions. The isomerisation process is found to be acid dependent, despite the absence of protonation under the conditions used, and presumably proceeds via an azo-type tautomer of the ligand. In all cases the existence of outer-sphere interaction processes has been established, both promoting the reactions and producing dead-end complexes. has also been conducted with significant differences in the kinetic features that implicate keystone outer-sphere interactions which dominate reactivity, even with isomeric forms that are not the best suited for direct complexation.

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“…There has been significant progress in the development of new generations of iron chelators, both for use in iron overload disease and for their antiproliferative activity in the inhibition of tumor growth (Yu et al, 2006(Yu et al, , 2009Richardson et al, 2009). Compounds that have been developed for such purposes include tridentate ligands such as those of the pyridoxal isonicotinoyl hydrazone (PIH) class that possess very high affinity for iron and much lower affinity for other essential metals, e.g., Zn(II), Mg(II), and Ca(II) (Richardson and Ponka, 1998a).…”

Section: Introductionmentioning

confidence: 99%

Potent Antimycobacterial Activity of the Pyridoxal Isonicotinoyl Hydrazone Analog 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone: A Lipophilic Transport Vehicle for Isonicotinic Acid Hydrazide

et al. 2013

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The rise in drug-resistant strains of Mycobacterium tuberculosis is a major threat to human health and highlights the need for new therapeutic strategies. In this study, we have assessed whether high-affinity iron chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class can restrict the growth of clinically significant mycobacteria. Screening a library of PIH derivatives revealed that one compound, namely, 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH), exhibited nanomolar in vitro activity against Mycobacterium bovis bacille Calmette-Guérin and virulent M. tuberculosis. Interestingly, PCIH is derived from the condensation of 2-pyridylcarboxaldehyde with the first-line antituberculosis drug isoniazid [i.e., isonicotinic acid hydrazide (INH)]. PCIH displayed minimal host cell toxicity and was effective at inhibiting growth of M. tuberculosis within cultured macrophages and also in vivo in mice. Further, PCIH restricted mycobacterial growth at high bacterial loads in culture, a property not observed with INH, which shares the isonicotinoyl hydrazide moiety with PCIH. When tested against Mycobacterium avium, PCIH was more effective than INH at inhibiting bacterial growth in broth culture and in macrophages, and also reduced bacterial loads in vivo. Complexation of PCIH with iron decreased its effectiveness, suggesting that iron chelation may play some role in its antimycobacterial efficacy. However, this could not totally account for its potent efficacy, and structureactivity relationship studies suggest that PCIH acts as a lipophilic vehicle for the transport of its intact INH moiety into the mammalian cell and the mycobacterium. These results demonstrate that ironchelating agents such as PCIH may be of benefit in the treatment and control of mycobacterial infection.

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Thiosemicarbazones from the Old to New: Iron Chelators That Are More Than Just Ribonucleotide Reductase Inhibitors

Cited by 359 publications

References 173 publications

Methemoglobin Formation by Triapine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and Other Anticancer Thiosemicarbazones: Identification of Novel Thiosemicarbazones and Therapeutics That Prevent This Effect

Methemoglobin Formation by Triapine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and Other Anticancer Thiosemicarbazones: Identification of Novel Thiosemicarbazones and Therapeutics That Prevent This Effect

Biologically active thiosemicarbazone Fe chelators and their reactions with ferrioxamine B and ferric EDTA; a kinetic study

Potent Antimycobacterial Activity of the Pyridoxal Isonicotinoyl Hydrazone Analog 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone: A Lipophilic Transport Vehicle for Isonicotinic Acid Hydrazide

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