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y = 0.96483 + 5.4611x R= 0.82892
y = 0.94145 + 5.4567x R= 0.81426
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0.30
kapp for complex stability
Figure 2. Correlation of cleavable complex stability with growth
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complexes. Our previous studies had suggested that
hydrophilic substituents at the 7-position resulted in
more stable cleavable complexes.30 Clearly, our data
on the 7-aryl-MD- analogs suggests that hydrophilicity
is not a requirement for complex stability. Instead, the
substituent at the 7-position may be required to interact
with specific residues of topo I within the cleavable com-
plex.35 It should be noted, however, that the aqueous
solubility of the 7-aryl-MD- analogs is poor. For exam-
ple, in Fig. 1B (at 0min), achieving 100% entrapment of
topo I on DNA was not feasible due to the limiting sol-
ubility of the 7-p-trifluoromethylphenyl-MD-CPT analog.
The use of very hydrophobic, 7-substituted CPT as anti-
tumor drugs would require an appropriate balance
among hydrophobicity for good cellular accumulation,
substituents that do not destabilize cleavable complexes,
and water solubility for formulation. The analogs de-
scribed in this report are the first of a class of analogs
with bulky, hydrocarbon groups directly attached to
the 7-position of camptothecin (e.g., 7-cyclohexyl-
CPT), and provide a methodological template for addi-
tional modifications to these hydrocarbons that could be
used to achieve the desired balance of properties for
novel antitumor agents.
17. Van Hattum, A. H.; Pinedo, H. M.; Schluper, H. M.;
Hausheer, F. H.; Boven, E. Int. J. Cancer 2000, 88, 260.
18. Bom, D.; Curran, D. P.; Zhang, J.; Zimmer, S. G.; Bevins,
R.; Kruszewski, S.; Howe, J. N.; Bingcang, A.; Latus, L.
J.; Burke, T. G. J. Controlled Release 2001, 74, 325.
19. De Cesare, M.; Pratesi, G.; Perego, P.; Carenini, N.;
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Vesci, L.; Pace, S.; Capocasa, F.; Carminati, P.; Zunino,
F. Cancer Res. 2001, 61, 7189.
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Acknowledgements
25. Wani, M. C.; Nicholas, A. W.; Manijumar, G.; Wall,
M. E. J. Med. Chem. 1987, 30, 1774.
26. Wani, M. C.; Nicholas, A. W.; Wall, M. E. J. Med. Chem.
1987, 30, 2317.
This work was partially supported by DHHS Grant R01
CA076563. The authors wish to thank Nancy Ruth Jar-
badan for her excellent technical assistance.
27. Bom, D.; Curran, D. P.; Kruszewski, S.; Zimmer, S. G.;
Thompson Strode, J.; Kohlhagen, G.; Du, W.; Chavan, A.
J.; Fraley, K. A.; Bingcang, A. L.; Latus, L. J.; Pommier,
Y.; Burke, T. G. J. Med. Chem. 2000, 43, 3970.
28. Dallavalle, S.; Ferrari, A.; Biasotti, B.; Merlini, L.; Penco,
S.; Gallo, G.; Marzi, M.; Tinti, M. O.; Martinelli, R.;
Pisano, C.; Carminati, P.; Carenini, N.; Beretta, G.;
References and notes
1. Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmar, K. H.;
MacPhail, A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88,
3888.