3270
L. Covassin et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3267–3271
observed for BNSD-X and BSM-X, which both bear
four aminopropyl groups, and BSD-X, in which two
aminopropyl groups can face each other on the opposite
ends of the cross-linker (Table 1).
9. Huber, M.; Pelletier, J.; Torossian, K.; Dionne, P.; Gama-
che, I.; Charest-Gaudreault, R.; Audette, M.; Poulin, R. J.
Biol. Chem. 1996, 271, 27556.
10. Seiler, N.; Sarhan, S.; Grauffel, C.; Jones, R.; Knodgen,
B.; Moulinoux, J.-P. Cancer Res. 1990, 50, 5077.
11. Leveque, J.; Burtin, F.; Catros-Quemener, V.; Havouis,
R.; Moulinoux, J. P. Anticancer Res. 1998, 18, 2663.
12. Hessels, J.; Kingma, A. W.; Ferwerda, H.; Keij, J.; Van
der Berg, G. A.; Muskiet, F. A. J. Int. J. Cancer 1989, 43,
1155.
13. Belting, M.; Borsig, L.; Fuster, M. M.; Brown, J. R.;
Persson, L.; Fransson, L. A.; Esko, J. D. Proc. Natl. Acad.
Sci. U.S.A. 1999, 99, 371. Belting, M.; Persson, S.; Fransson,
L. A. Biochem. J. 2002, 338, 317.
14. Persson, L.; Holm, I.; Ask, A.; Heby, O. Cancer Res.
1992, 48, 4807. Ask, A.; Persson, L.; Heby, O. Cancer Lett.
1992, 66, 29.
15. Covassin, L.; Desjardins, M.; Charest-Gaudreault, R.;
Audette, M.; Bonneau, M. J.; Poulin, R. Bioorg. Med. Chem.
Lett. 1999, 29, 1709. Covassin, L.; Bonneau, M.-J.; Desjar-
dins, M.; Lakhlef, R.; Audette, M.; Charest-Gaudreault, R.;
Poulin, R. Manuscript in preparation.
Covalent linking of the central amino group of tria-
mines to a benzyl strongly decreases the efficiency of
polyamine transport inhibition.30ꢀ34 Therefore, to
account for the structure–activity relationships of the
putrescine dimers, the decrease in transport antagonism
that is conferred to any single polyamine chain by
introducing the p-xylyl cross-linker must be counter-
acted by additional binding interactions afforded by the
presence of the second polyamine chain. Accordingly, a
cross-linker of optimal length and structure such as the
p-xylyl chain15 could be viewed as a ‘hinge’ allowing the
simultaneous and cooperative interaction of both dia-
mine or polyamine chains of the dimers. Moreover, the
efficiency of the latter interaction should be a function
of the electrostatic repulsion between the two positively
charged chains, and of additional conformations made
possible by the formation of intramolecular hydrogen
bonds and/or hydrophobic interactions. Thus, the sec-
ond polyamine chain introduced by dimerization of a
triamine possessing suboptimal methylene backbone
lengths between cationic centers, such as the 6-6-TA,
might promote a more efficient binding to the poly-
amine carrier through such additional interactions, as in
the case of the putrescine-like dimers. Likewise, novel
conformational arrangements of the aminopropyl
chains resulting fromthe dimerization of spermine,
spermidine, and sym-norspermidine could be respon-
sible for the improved interaction with the spermidine
transporter observed for BSM-X, BSD-X, and BNSD-
X, respectively. Evidence for a role of intramolecular
hydrogen bonds in the efficiency of triamine binding
with the polyamine transporter has already received
16. Minchin, R. F.; Martin, R. L.; Summers, L. A.; Ilett, K. F.
Biochem. J. 1989, 262, 391.
17. Aziz, S. M.; Gosland, M. P.; Crooks, P. A.; Olson, J. W.;
Gillespie, M. N. J. Pharmacol. Exp. Ther. 1995, 274, 181.
18. Weeks, R. S.; Vanderwerf, S. M.; Carlson, C. L.; Burns,
M. R.; O’Day, C. L.; Cai, F.; Devens, B. H.; Webb, H. K.
Exp. Cell Res. 2000, 261, 293.
19. Burns, M. R.; Carlson, C. L.; Vanderwerf, S. M.; Ziemer,
J. R.; Weeks, R. S.; Cai, F.; Webb, H. K.; Graminski, G. F. J
Med. Chem. 2001, 44, 3632.
20. Graminski, G. F.; Carlson, C. L.; Ziemer, J. R.; Cai, F.;
Vermeulen, N. M.; Vanderwerf, S. M.; Burns, M. R. Bioorg.
Med. Chem. Lett. 2002, 12, 35.
21. Bergeron, R. J.; Burton, P. S.; McGovern, K. A.; Kline,
S. J. Synthesis 1981, 9, 732.
22. Bergeron, R. J.; Feng, Y.; Weimar, W. R.; McManis, J. S.;
Dimova, H.; Porter, C.; Raisler, B.; Phanstiel, O. J. Med.
Chem. 1997, 40, 1475.
23. Zang, E.; Sadler, P. J. Synth. Commun. 1997, 27, 3145.
24. Krakowiak, K. E.; Bradshaw, J. S. Synth. Commun. 1998,
28, 3451.
8,32
experimental support.
25. Bis (hexamethylene)triamine (6-6-TA) was obtained from
Aldrich (Milwaukee, WI, USA). The following compounds were
characterized by 1H NMR spectroscopy: 4-4-TA: 1H NMR
(CDCl3) d 2.55 and 2.45 (2t, 8H, 2ꢃCH2NI, 2ꢃCH2NII); 1.2–
1.5 (m, 8H, 4ꢃCH2); 1.1 (m, 5H, 1ꢃNH, 2ꢃNH2); 5-5-TA:
(CDCl3) d 2.45 and 2.36 (2t, 8H, 2ꢃCH2NI, 2ꢃCH2NII); 1.10–
1.32 (m, 12H, 6ꢃCH2); 0.95 (m, 5H, 1ꢃNH, 2ꢃNH2) (B-4-4-
X:. 1H NMR (D2O) d 7.6 (s, 4H, aromatic-H), 4.25 (s, 4H,
2ꢃCH2Ph), 3.15 and 2.9 (2m, 16H, 8ꢃCH2N), 1.5–1.9 (m,
16H, 8ꢃCH2); B-5-5-X: 1H NMR (D2O) d 7.55 (s, 4H, aro-
matic-H), 4.3 (s, 4H, 2ꢃCH2Ph), 3.05 and 2.85 (2m, 16H,
8ꢃCH2N), 1.5–1.8 (m, 16H, 8ꢃCH2), 1.3 (m, 8H, 4ꢃCH2); B-
6-6-X: 1H NMR (D2O) d 7.59 (s, 4H, aromatic-H), 4.39 (s, 4H,
2ꢃCH2Ph), 3.12 (m, 8H, 4ꢃCH2N), 2.95 (t, 8H, 4ꢃCH2NH2,
J=7.6 Hz), 1.55–1.75 (m, 16H, 8ꢃCH2), 1.1–1.3 (m, 16H,
8ꢃCH2); BSM-X: 1H NMR (D2O) d 7.61 (s, 4H, aromatic-H),
4.45 (s, 4H, 2ꢃCH2Ph), 3.25 (m, 8H, 4ꢃCH2NIII), 2.95–3.15
(m, 16H, 4ꢃCH2NII, 4ꢃCH2NI), 2.00–2.15 (m, 8H, 4ꢃCH2),
1.85 (m, 4H, 2ꢃCH2), 1.73 (m, 4H, 2ꢃCH2).
Acknowledgements
This work was supported by Strategic Grant
STR0181460 fromthe Natural Sciences and Engineer-
ing Council of Canada and by a sponsorship from
ILEX Oncology Inc. (San Antonio, TX, USA).
References and Notes
1. Marton, L. J.; Pegg, A. E. Annu. Rev. Pharmacol. Toxicol.
1995, 35, 55.
2. Cohen, S. S. A Guide to the Polyamines; Oxford University
Press: New York, 1998.
3. Seiler, N.; Dezeure, F. Int. J. Biochem. 1990, 22, 211.
4. Seiler, N.; Delcros, J. G.; Moulinoux, J. P. Int. J. Biochem.
Cell. Biol. 1996, 28, 843.
5. Pegg, A. E.; Poulin, R.; Coward, J. K. Int. J. Biochem. Cell.
Biol. 1995, 27, 425.
26. Kawata, S.; Kosugi, H.; Uda, H.; Iwaisumi, M.; Yokoi,
H. Bull. Chem. Soc. Jpn. 1992, 65, 2910.
6. McCann, P. P.; Pegg, A. E. Pharm. Ther. 1992, 54, 195.
7. Pegg, A. E.; Shantz, L. M.; Coleman, C. S. J. Cell Biochem.
1995, 132.
8. Lessard, M.; Zhao, C.; Singh, S. M.; Poulin, R. J. Biol.
Chem. 1995, 270, 1685.
27. Johns, B. A.; Pan, Y. T. D. E.A.; Johnson, C. R. J. Am.
Chem. Soc. 1997, 119, 4856.
28. BPO-X:. 1H NMR (CDCl3) d 7.2 (m, 4H, aromatic-H),
4.4 (m, 4H, 2ꢃCH2Ph), 3.3 (m, 2H, 2ꢃCH), 2.8 (m, 8H,
4ꢃCH2N), 2.4–2.6 (m, 4H, 2ꢃCH2), 1.0 (br s, 8H, 4ꢃNH2);