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Blood, 15 July 2002, Vol. 100, No. 2, pp. 666-676
RED CELLS
Novel "hybrid" iron chelators derived from aroylhydrazones
and thiosemicarbazones demonstrate selective antiproliferative
activity against tumor cells
David B. Lovejoy and
Des R. Richardson
From the Heart Research Institute, The Iron Metabolism
and Chelation Group, Camperdown, Sydney, New South Wales, Australia.
We previously demonstrated that
2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311)
and other aroylhydrazone chelators possess potent antineoplastic
activity because of their ability to bind iron (Fe). From these
studies, we identified structural components of the hydrazones that
provide antineoplastic activity, namely the salicylaldehyde and
2-hydroxy-1-naphthylaldehyde moieties. A related group of chelators
known as the thiosemicarbazones also show pronounced antitumor activity
because of their ability to inhibit ribonucleotide reductase.
Considering this, we designed a new series of "hybrid ligands" by
condensation of the aldehydes described above with a range of
thiosemicarbazides. The parent compound of these ligands is
2-hydroxy-1-naphthylaldehyde thiosemicarbazone (NT). Of 8 NT
analogues, 3 chelators, namely NT, N4mT
(2-hydroxy-1-naphthylaldehyde-4-methyl-3-thiosemicarbazone), and
N44mT
(2-hydroxy-1-naphthylaldehyde-4,4-dimethyl-3-thiosemicarbazone), showed high antiproliferative activity against SK-N-MC neuroepithelioma cells (50% inhibitory concentration
[IC50] = 0.5-1.5 µM). Indeed, their activity was
significantly (P < .0001) greater than that of
desferrioxamine (DFO) (IC50 = 22 µM). We demonstrate
that 311, a 311 analogue (311m), and several NT-series chelators have
significantly (P < .001) greater antiproliferative
activity against tumor cells than against a range of normal cell types.
For example, the IC50 values of NT and N4mT in SK-N-MC
neuroepithelioma cells were 0.5 µM, whereas for fibroblasts
the IC50 values were greater than 25 µM. Further, the
effect of one of the most potent chelators (311m) on preventing the
growth of bone marrow stem cell cultures was far less than that of
doxorubicin and similar to that of cisplatin. These studies support the
further development of these chelators as antiproliferative agents.
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