To achieve cellular iron deprivation by chelation, it is important to develop chelators with selective metal-binding properties. Selectivity for iron has long been the province of certain oxygen-donor chelators such as desferrioxamine, which target Fe(III) and exploit the strength of a relatively ionic Fe(III)-O interaction. We have been studying novel chelators that possess mechanisms to selectively chelate + 2 biometals, particularly tachpyr [N,N′,N″-tris(2-pyridylmethyl)-1,3,5-cis,cis-triaminocyclohexane] and derivatives from N, N′, N″-trialkylation and pyridine ring alkylation. Metal-exchange and metal-binding competition reactions have been conducted at pH 7.4, 37°C and time periods until no further change was observed (generally 24–48 h). Under anaerobic conditions, tachpyr is strongly selective for iron, binding 95±5% Fe(II) versus 5±5% Zn(II) in the forms [Fe(tachpyr)]2+ and [Zn(tachpyr)]2+ respectively. Under aerobic conditions, tachpyr complexes Fe(II) more effectively than Fe(III), forming iminopyridyl complexes [Fe(tachpyrox-n)]2+ (n = 2,4) by O2-induced and ironmediated oxidative dehydrogenation. Complexes [Fe(tachpyr-ox-n)]2+ are also strongly bound forms of iron that are unaffected by an excess of Zn(II) (75 mol zinc:1 mol iron complex). The preference of tachpyr for iron over zinc under aerobic conditions appears to be hindered by oxidation of Fe(II) to Fe(III), such that the proportions bound are 44±10% Fe(II) versus 56±10% Zn(II), in the respective forms [Fe(tachpyr-ox-n)]2+ and [Zn(tachpyr)]2+. However, upon addition of the reducing agent Na2S2O4 that converts Fe(III) to Fe(II), the binding proportions shift to 76±10% Fe(II) versus 24±10% Zn(II), demonstrating a clear preference of tachpyr for Fe(II) over Zn(II). Iron(II) is in the low-spin state in [Fe(tachpyr)]2+ and [Fe(tachpyr-oxn)]2+ (n = 2, 4), which is a likely cause of the observed selectivity. N-methylation of tachpyr [giving (N-methyl)3tachpyr] results in the loss of selectivity for Fe(II), which is attributed to the steric effect of the methyl groups and a resulting high-spin state of Fe(II) in [Fe(N-methyl)3tachpyr)]2+. The relationship of chelator selectivity to cytotoxicity in the tach family will be discussed.
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August 2002
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Conference Article|
August 01 2002
Novel cytotoxic chelators that bind iron(II) selectively over zinc(II) under aqueous aerobic conditions
R. P. Planalp;
R. P. Planalp
1
*Department of Chemistry, University of New Hampshire, Durham, NH 03824-3598, U.S.A.
1To whom correspondence should be addressed (e-mail roy.planalp@unh.edu)
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A. M. Przyborowska;
A. M. Przyborowska
*Department of Chemistry, University of New Hampshire, Durham, NH 03824-3598, U.S.A.
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G. Park;
G. Park
*Department of Chemistry, University of New Hampshire, Durham, NH 03824-3598, U.S.A.
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N. Ye;
N. Ye
*Department of Chemistry, University of New Hampshire, Durham, NH 03824-3598, U.S.A.
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F. H. Lu;
F. H. Lu
†Radiation Oncology Branch, National Institutes of Health, Bethesda, MD 20892-1002, U.S.A.
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R. D. Rogers;
R. D. Rogers
‡Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487, U.S.A.
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G. A. Broker;
G. A. Broker
‡Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487, U.S.A.
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S. V. Torti;
S. V. Torti
§Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, U.S.A.
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M. W. Brechbiel
M. W. Brechbiel
†Radiation Oncology Branch, National Institutes of Health, Bethesda, MD 20892-1002, U.S.A.
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Publisher: Portland Press Ltd
Received:
March 20 2002
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2002 Biochemical Society
2002
Biochem Soc Trans (2002) 30 (4): 758–761.
Article history
Received:
March 20 2002
Citation
R. P. Planalp, A. M. Przyborowska, G. Park, N. Ye, F. H. Lu, R. D. Rogers, G. A. Broker, S. V. Torti, M. W. Brechbiel; Novel cytotoxic chelators that bind iron(II) selectively over zinc(II) under aqueous aerobic conditions. Biochem Soc Trans 1 August 2002; 30 (4): 758–761. doi: https://doi.org/10.1042/bst0300758
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