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(2) Reaction with biological nucleophiles (DNA, protein). this study. This work was supported by a Discovery grant from
This applies for 3.
the Natural Sciences and Engineering Research Council of
Canada (to G. I. D.), the Canadian Institutes of Health Research
and a Canada Research Chair in Drug Development grants
(to B.B.H.) and an American Chemical Society Petroleum
Research Fund grant (to V.B.B.). An Ontario Graduate Scholar-
ship (to G.L.A.) is gratefully acknowledged.
Notes and references
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3) Non-covalent binding to a biological receptor which is
possible for both 4 and 3. In the case of kinamycin F, a recent
study involving this laboratory has revealed that kinamycin F may
be specically targeting a protein involved in transcription of
cyclin D3, one of a group of proteins involved in the cell cycle. The
contribution of such an interaction to the overall MOA of kin-
amycin F is unlikely to be the consequence of a non-selective DNA
cleavage event. A non-covalent or possibly a covalent binding to
such a protein target by kinamycin F or one of its metabolites
might explain the cytotoxicity since the diminution of cyclin D3
levels is known to induce apoptosis (programmed cell death). It is
not yet known if similar effects on cyclin D3 levels are induced by
prekinamycin, isoprekinamycin or the lomaiviticins.
One interpretation of the comparable cytotoxicity of 4 and 3 is
that for 4, the electron transfer MOA makes a better contribution
to the cytotoxicity effect, whereas for 3 the reaction with biolog-
ical nucleophiles may be more important. Another interesting
observation is the very low activity of the ketone 22. In the kin-
amycin series, the dimeric analogues called the lomaiviticins 6
possess such a keto group and are very active in DNA cleavage
experiments under reducing conditions and are highly cytotoxic
to cancer cells; more so than the monomeric kinamycins that
lack the keto group. It is not clear, however, if the O-methyl group
might play a role in the low activity of 22. This speculation is
borne out by Herzon's recent observations in which kinamycin
analogues bearing methoxy substituents displayed cytotoxicity
that was substantially lower than values obtained from the cor-
33
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This study has provided some insight into the similarity and
differences between the N-cyanobenzo[b]carbazole-based
structure originally assigned to the kinamycins and the cor-
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rected (diazobenzo[b]uorene-based) structure assigned more
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recently. We conclude that there is sufficient similarity
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carbazole-type analogues of the kinamycins. Synthetic efforts
aimed at accessing such analogues are in progress.
21 K. A. O'Hara, X. Wu, D. Patel, H. Liang, J. C. Yalowich,
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Acknowledgements
3 W. Zeng, T. E. Ballard, A. G. Tkachenko, V. A. Burns,
D. L. Feldheim and C. Melander, Bioorg. Med. Chem. Lett.,
2006, 16, 5148–5151.
Mrs Valerie Goodfellow, Dr Nan Chen and Dr Otunola Adedayo
are thanked for generating the sample of kinamycin F used in
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