ANTHRAQUINONES AS INHIBITORS OF HUMAN TELOMERASE
671
inhibited the related enzyme, Taq polymerase, at
concentrations up to 50 mM, suggesting selective
inhibition of telomerase.
Sunderland, and Dr L. R. Kelland, CRC, Sutton, for
helpful discussions.
The general cytotoxicity data for the synthesized
anthraquinones are shown in Tables 2 and 3 . With
the exception of compounds 1,4AC and 1,5AC, all
of the compounds were remarkably non-toxic in all
of the tested ovarian carcinoma cell lines. It appears
that the compounds substituted with the N,N-
diethylaminoethylamino sidechain (1,4AC and
1,5AC) display greater cytotoxicity than the cor-
responding hydroxypentylamino substituted com-
pounds. This may in part be due to the presence of
an ionizable nitrogen in the sidechain of 1,4AC and
1,5AC, which will stabilize interaction with the
polyanionic backbone of DNA leading to non-
speci®c cell toxicity. The 1,8 disubstituted com-
pound, 1,8AC, appears anomalous in that it
demonstrates signi®cant inhibition of human telo-
merase at a concentration of 10 mM with no asso-
ciated cell toxicity even though it possesses the
ionizable N,N-diethylaminoethylamino sidechain.
This may be due to the fact that 1,8-disubstituted
anthraquinones can only intercalate with the long
axis of the chromophore aligned parallel to the
base-pair axis. The other disubstituted anthraqui-
nones are unable to intercalate in this way (Islam et
al 1985). Alternatively, the telomerase inhibition of
these compounds may be mediated through a non-
speci®c inhibition of the enzyme which is unrelated
to intercalation.
References
Blackburn, E. H. (1991) Structure and function of telomeres.
Nature 350: 569±573
Gibson, V., Anderson, R. J., Brown, J. R., Hartley, J. A.,
Cassidy, S. A., Fox, K. R., Cairns, D. (1996) Anthraqui-
none±oligodeoxynucleotide conjugates as triple helix stabi-
lizing agents. Pharm. Sci. 2: 49±53
Islam, S. A., Neidle, S., Gandecha, B. M., Patterson, L. H.,
Brown, J. R. (1985) Comparative computer graphics and
solution studies of the DNA interaction of substituted
anthraquinones based on doxorubicin and mitoxantrone.
J. Med. Chem. 28: 857±864
Kelland, L. R., Abel, G., McKeage, M. J., Jones, M., Goddard,
P., Valenti, M., Murrer, B. A., Harrap, K. R. (1993)
Preclinical antitumour evaluation of bis-acetato-amine-
dichloro-cyclohexylamine platinum (IV): an orally active
platinum drug. Cancer Res. 53: 2581±2586
Kim, N. W., Piatyszek, M. A., Prowse, K. R., Harley, C. B.,
West, M. D., Ho, P. L. C., Coviello, G. M., Wright, W. E.,
Weinrich, R. L., Shay, J. W. (1994) Speci®c association of
human telomerase activity with immortal cells and cancer.
Science 266: 2011±2015
Perry, P. J., Kelland, L. R. (1998) Telomeres and telomerase:
targets for cancer chemotherapy. Exp. Opin. Ther. Patents 8:
1567±1586
Perry, P. J., Gowan, S. M., Reszka, A. P., Polucci, P., Jenkins,
T. C., Kelland, L. R., Neidle, S. (1998) 1,4- and 2,6-
amidoanthracene-9,10-dione
as inhibitors of human telomerase. J. Med. Chem. 41:
3253±3260
Perry, P. J., Read, M. A., Davies, R. T., Gowan, S. M., Reszka,
A. P., Wood, A. A., Kelland, L. R., Neidle, S. (1999) 2,7-
Disubstituted amido¯uorenone derivatives as inhibitors of
human telomerase. J. Med. Chem. 42: 2679±2684
Raymond, E., Sun, D., Chen, S. -F., Windle, B., von Hoff, D.
D. (1996) Agents that target telomerase and telomeres. Curr.
Opin. Biotechnol. 7: 583±591
Disubstituted
derivatives
Previous work has proposed that anthraquinone
derivatives inhibit telomerase by intercalation into
G-quadruplex structures associated with telomeric
DNA (Sun et al 1997). Molecular modelling studies
are currently underway in our laboratories to
investigate this phenomenon.
Sun, D., Thompson, B., Cathers, B. E., Salazar, M., Kerwin, S.
M., Trent, J. O., Jenkins, T. C., Neidle, S., Hurley, L. H.
(1997) Inhibition of human telomerase by a G-quadruplex-
interactive compound. J. Med. Chem. 40: 2113±2116
Acknowledgements
We are grateful to Dr S. P. Mackay, Institute
of Pharmacy and Chemistry, University of