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9. Studies on the synthesis,
characterization and binding with DNA of cis-bis(2,3-diaminopyridine)diiodoplatinum(II):
A compound with high cell uptake and drug-DNA binding but very little
activity
Fazlul Huq*1,
Ahmed Abdullah1, Philip Beale2, Jun Qing Yu1
and Mei Zhang2
1School
of Biomedical Sciences, Cumberland Campus, C42, The University of
Sydney,
f.huq@fhs.usyd.edu.au
2RPAH,
Missenden Road, Camperdown NSW, Australia
(Received 30 November 2005; accepted
12 February 2006)
Abstract:
cis-PtL2I2
where L is 2,3-diaminopyridine,
code named AH8, has been synthesized and characterized by elemental
analyses and spectral studies. The interaction of AH8 and cisplatin
with pBR322 plasmid DNA has been studied and activity of the compound
against human ovarian cell lines: A2780, A2780cisR and
A2780ZD0473R have been determined. AH8 is found to cause
much less conformational change and damage to pBR322 plasmid DNA than
cisplatin and to be totally inactive although it has cell uptake and
level of binding with cellular DNA. Whereas cisplatin binds with DNA
forming predominantly intrastrand Pt(GG) adduct that causes local
bending of a DNA strand towards the major groove and consequently
exposing a wide and shallow minor groove surface to several classes of
proteins including high-mobility group box proteins, AH8 is expected
to form mainly monofunctional Pt(G) and Pt(A) adducts and DNA-Pt-protein
crosslinks. The low degree of dissociation of AH8 explains why it has
a high cell uptake and the absence of critical intrastrand
bifunctuional 1,2-Pt(GG) adduct explains why the compound is inactive.
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