ORGANIC
LETTERS
2
010
Vol. 12, No. 15
488-3490
Facile Dimer Synthesis for DNA-Binding
Polyamide Ligands
3
Modi Wetzler and David E. Wemmer*
Chemimstry Department, UniVersity of California, Berkeley, California 94720
Received June 9, 2010
ABSTRACT
Pyrrole-imidazole polyamide ligands are highly sequence specific synthetic DNA-binding ligands that bind with high affinity. To counter the synthetic
difficulties associated with coupling the electron-rich heterocyclic acids to the electron-deficient nucleophilic imidazole amine, a novel approach is
described for synthesis of Fmoc-protected dimers for solid-phase peptide synthesis (SPPS). This method produces the dimers in high yields, is
broadly applicable to other heterocyclic-containing polyamides, and results in improved ligand yields and synthesis times.
2
,3
Synthetic polyamide ligands containing N-methylpyrrole (Py)
and N-methylimidazole (Im) have affinity and specificity for
Both SPPS ligand synthesis and solution dimer synthesis
2
for SPPS couple an amino-protected monomer (1 or 2) to
1
DNA similar to DNA binding proteins. Over the past decade
a resin-bound amine or an amine-bearing monomer (3 or 4,
Figure 1). However, the imidazole amine 4 is a poor
nucleophile, with reported yields as low as 5% for on-resin
2
preparation of these ligands through standard Boc- and
3
Fmoc-based solid-phase peptide synthesis (SPPS) techniques
has been described.
10
coupling. Common synthetic approaches include varying
Due to the increasing complexity and length of recently
3,11,12
13
the activation chemistry,
heating the resin, or pro-
4
reported DNA-binding ligands, faster methods to access these
11,13
longing individual coupling steps to as long as 60 h.
However, none of these strategies directly address the
inherent difficulty of coupling an electron-rich electrophile
to an electron-poor nucleophile.
increasingly complicated molecules in fewer steps would save
both time and purification effort. Furthermore, the continued
use of solution-based synthesis for these ligands in recent
5-9
years
demonstrates that significant room remains for
improving their synthetic accessibility with use of SPPS.
(8) Mackay, H.; Brown, T.; Uthe, P. B.; Westrate, L.; Sielaff, A.; Jones,
(
1) Dervan, P. B.; Poulin-Kerstien, A. T.; Fechter, E. J.; Edelson, B. S.
J.; Lajiness, J. P.; Kluza, J.; O’Hare, C.; Nguyen, B.; Davis, Z.; Bruce, C.;
Wilson, W. D.; Hartley, J. A.; Lee, M. Bioorg. Med. Chem. 2008, 16, 9145–
9153.
Curr. Med. Chem. 2005, 253, 1–31.
(
2) Baird, E. E.; Dervan, P. B. J. Am. Chem. Soc. 1996, 118, 6141–
6
146.
(9) Kotecha, M.; Kluza, J.; Wells, G.; O’Hare, C. C.; Forni, C.;
Mantovani, R.; Howard, P. W.; Morris, P.; Thurston, D. E.; Hartley, J. A.;
Hochhauser, D. Mol. Cancer Ther. 2008, 7, 1319–1328.
(10) Su, W.; Gray, S. J.; Dondi, R.; Burley, G. A. Org. Lett. 2009, 11,
3910–3913.
(
3) Wurtz, N. R.; Turner, J. M.; Baird, E. E.; Dervan, P. B. Org. Lett.
2
001, 3, 1201–1203.
(4) Edayathumangalam, R. S.; Weyermann, P.; Gottesfeld, J. M.; Dervan,
P. B.; Luger, K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6864–6869.
5) Westrate, L.; Mackay, H.; Brown, T.; Nguyen, B.; Kluza, J.; Wilson,
W. D.; Lee, M.; Hartley, J. A. Biochemistry 2009, 48, 5679–5688
6) Breen, D.; Kennedy, A. R.; Suckling, C. J. Org. Biomol. Chem. 2009,
, 178–186
7) Simon, P.; Cannata, F.; Perrouault, L.; Halby, L.; Concordet, J. P.;
Boutorine, A.; Ryabinin, V.; Sinyakov, A.; Giovannangeli, C. Nucleic Acids
Res. 2008, 36, 3531–3538
(
(11) Buchmueller, K. L.; Taherbhai, Z.; Howard, C. M.; Bailey, S. L.;
Nguyen, B.; O’Hare, C.; Hochhauser, D.; Hartley, J. A.; Wilson, W. D.;
.
(
Lee, M. ChemBioChem 2005, 6, 2305–2311
.
7
.
(12) Sasaki, S.; Bando, T.; Minoshima, M.; Shimizu, T.; Shinohara, K.-
(
i.; Takaoka, T.; Sugiyama, H. J. Am. Chem. Soc. 2006, 128, 12162–12168.
(13) Doss, R. M.; Marques, M. A.; Foister, S.; Chenoweth, D. M.;
.
Dervan, P. B. J. Am. Chem. Soc. 2006, 128, 9074–9079.
10.1021/ol1013262 2010 American Chemical Society
Published on Web 07/13/2010