C. A. Price et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3151–3156
3155
DÕIncalci, M.; Broggini, M. Br. J. Cancer 1999, 80, 338; (c)
Wang, D. G.; Lander, E. S. Science 1998, 280, 1077; (d)
Evans, W. E.; Relling, M. V. Science 1999, 286, 487; (e)
Bunk, S. The Scientist 2002, 16, 13.
was seen at A(411). The sequence preference of hairpin 1
for 50-TCA (411)-30 on the topoisomerase IIa fragment
is consistent with the 50-TCA(888)-30 preference ob-
served from the pUC18 experiment. Likewise, the pref-
erence of hairpin 2 for 50-CTA(422)-30 agrees with the
50-CAA(857)-30, in which the Py/Bf could bind either
an A/T or T/A base pair.
3. (a) Neidle, S. DNA Structure and Recognition; IRL:
Oxford, 1994; (b) Molecular Aspects of Anticancer Drug–
DNA Interaction; Neidle, S., Waring, M., Eds.; CRC:
Boca Raton, 1993; Vol. 1; (c) Molecular Aspects of
Anticancer Drug–DNA Interaction; Neidle, S., Waring,
M., Eds.; CRC: Boca Raton, 1994; Vol. 2; (d) Nucleic Acid
Targeted Drug Design; Propst, C. L., Perun, T. J., Eds.;
Marcel Dekker: New York, 1992; (e) Advances in DNA
Sequence-Specific Agents; Hurley, L. H., Ed.; JAI: Green-
wich, 1992; Vol. 1; (f) Advances in DNA Sequence-Specific
Agents; Jones, G. B., Palumbo, M., Eds.; JAI: Greenwich,
1998; Vol. 3; (g) Neidle, S.; Thurston, D. E. In New
Molecular Targets for Cancer Chemotherapy; Kerr, D. J.,
Workman, P., Eds.; CRC: Boca Raton, 1994, pp 159–
175.
4. (a) Dervan, P. B. Science 1986, 232, 464; (b) Dervan, P. B.;
Edelson, B. S. Curr. Opin. Struct. Biol. 2003, 13, 284; (c)
Krowicki, K.; Lee, M.; Hartley, J. A.; Ward, B.; Kissinger,
K.; Skorobogaty, A.; Dabrowiak, J. C.; Lown, J. W.
Struct. Express. 1988, 2, 251; (d) Kopka, M. L.; Goodsell,
D. S.; Han, G. W.; Chiu, T. K.; Lown, J. W.; Dickerson,
R. E. Structure 1997, 5, 1033; (e) DNA and RNA binders;
Demeunynck, M., Bailly, C., Wilson, W. D., Eds.; Wiley-
VCH: Germany, 2003.
Models that depict the molecular interactions of hairpin
conjugates 1–3 with the 50-TCA(888)G-30, 50-CA-
A(857)C-30, and 50-TTA(843)C-30 sequences, found in
the pUC18 plasmid are shown in Figure 4. In these
models, the compounds are oriented toward the 50 direc-
tion from the alkylation site. This orientation is consis-
tent with the previously reported model of a complex of
compound (S)-4 with the 30-GGGA(888)CTGCTC-50
sequence, in which the imidazole would stack with the
benzofuran to form a complex similar to that of the pyr-
role/imidazole pairing that is capable of recognizing a
C/G base pair.16a It is not likely that compounds 1–3
would bind to the three sequences in an extended con-
formation, because compounds 1 and 2 would require
the benzofuran group to bind unfavorably to a C/G
base pair. We have found that like seco-CI-TMI, the
achiral seco-CI-Bf also bound to the A(865) cluster
and not to GC-containing sites (data not shown).16a
Further support of the hairpin conformation of com-
pounds 1 and 2 came from a report that an aliphatic
dicarboxamide of polyamides, such as a bis-linked
netropsin with pimelic acid, was capable of forming a
hairpin structure.24
5. James, P. L.; Le Strat, L.; Ellervik, U.; Bratwall, C.;
Norden, B.; Brown, T.; Fox, K. R. Biophys. Chem. 2004,
111, 205.
6. Spackova, N.; Cheatham, T. E., III; Ryjacek, F.; Lankas,
F.; Van Meervelt, L.; Hobza, P.; Sponer, J. J. Am. Chem.
Soc. 2003, 125, 1759.
7. Nguyen, B.; Hamelberg, D.; Bailly, C.; Colson, P.; Stanek,
J.; Brun, R.; Neidle, S.; Wilson, W. D. Biophys. J. 2004,
86, 1028.
8. (a) Dervan, P. B.; Burlii, R. W. Curr. Opin. Chem. Biol.
1999, 3, 688; (b) Wemmer, D. E.; Dervan, P. B. Curr.
Opin. Struct. Biol. 1997, 7, 355; (c) Dervan, P. B. Bioorg.
Med. Chem. 2001, 9, 2215.
9. (a) Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed.
1996, 35, 1438; (b) Boger, D. L.; Johnson, D. S. Proc.
Natl. Acad. Sci. U.S.A. 1995, 92, 3642; (c) Boger, D. L.;
Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A. Chem.
Rev. 1997, 97, 787.
In summary, the studies described in this communica-
tion show that conjugates of duocarmycins and poly-
amides that can fold into a hairpin conformation are
capable of recognizing specific sequences of DNA.
More importantly, removal of the chiral center in the
duocarmycin-polyamide conjugates released the
compounds for a strong memory for the AAAAA(865)
sequence, thereby permitting the achiral hairpin
molecules for further structural refinement in order to
attain DNA sequence specificity. Current studies
on compounds 1–3 are focused on ascertaining the
nature by which they covalently react with DNA,
including isolation and characterization of purine-N3
adducts.9,19,21,22,25
10. Tomasz, M. Chem. Biol. 1995, 9, 575.
11. (a) Gregson, S. J.; Howard, P. W.; Gullick, D. R.;
Hamaguchi, A.; Corcoran, K. E.; Brooks, N. A.; Hartley,
J. A.; Jenkins, T. C.; Patel, S.; Guille, M. J.; Thurston, D.
E. J. Med. Chem. 2004, 47, 1161; (b) Cooper, N.; Hagan,
D. R.; Tiberghien, A.; Ademefun, T.; Matthews, C. S.;
Howard, P. W.; Thurston, D. E. Chem. Commun. 2002,
21, 1764.
Acknowledgements
12. (a) Wemmer, D. E. Biopolymers 2001, 52, 197; (b)
Wemmer, D. E. Annu. Rev. Biophys. Biomol. Struct.
2000, 29, 439.
13. Parks, M. E.; Baird, E. E.; Dervan, P. B. J. Am. Chem.
Soc. 1996, 118, 6147.
Financial support from Research Corporation, NSF-
REU (to M.L.), and Cancer Research UK (to J.A.H.)
is gratefully acknowledged. The authors also thank
Dr. Robert Kelly at Pharmacia & Upjohn for a gener-
ous gift of CC-1065.
14. Lee, M.; Rhodes, A. L.; Wyatt, M. D.; Forrow, S.;
Hartley, J. A. Biochemistry 1993, 32, 4237.
15. Buchmueller, K. L.; Staples, A. M.; Howard, C. M.;
Horick, S. M.; Uthe, P. B.; Le, N. M.; Cox, K. K.;
Nguyen, B.; Pacheco, K. A. O.; Wilson, W. D.; Lee, M. J.
Am. Chem. Soc. 2005, 127, 742.
References and notes
16. (a) Toth, J. L.; Price, C. A.; Madsen, E. C.; Handl, H. L.;
Hudson, S. J.; Hubbard, R. B., III; Bowen, P. J.; Kiakos,
K.; Hartley, J. A.; Lee, M. Bioorg. Med. Chem. Lett. 2002,
12, 2245; (b) Howard, T. T.; Lingerfelt, B. M.; Purnell, B.
1. Uil, T. G.; Haisma, H. J.; Rots, M. G. Nucleic Acids Res.
2003, 31, 6064.
2. (a) Janata, J.; Josowicz, M.; Vanysek, P.; DeVaney, D. M.
Anal. Chem. 1998, 70, 179R; (b) Colella, G.; Marchini, S.;