C O M M U N I C A T I O N S
Figure 2. Sensorgrams (resonance units vs time) for the binding of porphyrin 1 on duplex and quadruplex DNA at high chip loading (See Supporting
Information).
Table 1. Kinetic and Equilibrium Constants for the Interaction of 1
CT-2003-508842) and the Josef Steiner Cancer Research Award
2003.
with Quadruplex DNAa
1
1
1
kon (M-1 s-
)
koff (s-
)
Ka (M-
)
Supporting Information Available: Synthesis and characterization
of 1, surface plasmon resonance analysis, Scatchard plots corresponding
to Figure 2 and TRAP assay. This material is available free of charge
0.5 × 106
5 × 10-4
1 × 109
3.7 × 105
1 × 10-2
3.7 × 107
a Values in bold correspond to a site of higher affinity. Values are from
the data of Figure 3.
References
(1) (a) Wang, Y.; Patel, D. J. Structure 1993, 1, 263-282. (b) Parkinson,
G. N.; Lee, M. P. H.; Neidle, S. Nature 2002, 417, 876-880. (c) Ambrus,
A.; Chen, D.; Dai, J.; Bialis, T.; Jones, R. A.; Yang, D. Nucleic Acids
Res. 2006, 34, 2723-2735. (d) Luu, K. N.; Phan, A. T.; Kuryavyi, V.;
Lacroix, L.; Patel, D. J. J. Am. Chem. Soc. 2006, 128, 9963-9970.
(2) (a) Schaffitzel, C.; Berger, I.; Postberg, J.; Hanes, J.; Lipps, H. J.;
Plu¨ckthun, A. Proc. Natl. Acad. Sci. U.S.A. 2005, 98, 8572-8577. (b)
Paeschke, K.; Simonsson, T.; Postberg, J.; Rhodes, D.; Lipps, H. J. Nat.
Struct. Mol. Biol. 2005, 12, 847-854.
(3) Cech, T. R. Cell 2004, 116, 273-279.
(4) (a) Olaussen, K. A.; Dubrana, K.; Domont, J.; Spano, J.-P.; Sabatier, L.;
Soria, J.-C. Crit. ReV. Oncol. Haematol. 2006, 57, 191-214. (b) Blasco,
M. A. Nature ReV. Genet. 2005, 6, 611-622.
(5) (a) Neidle, S.; Parkinson, G. Nature ReV. Genet. 2002, 1, 383-393. (b)
Mergny, J.-L.; Riou, J.-F.; Mailliet, P.; Teulade-Fichou, M.-P.; Gilson,
E. Nucleic Acids Res. 2002, 30, 839-865. (c) Rezler, E. M.; Bearss,
D. J. Hurley, L. H. Curr. Opin. Pharmacol. 2002, 2, 415-423 and
references therein.
Figure 3. Sensorgrams (resonance units vs time) for the binding of
porphyrin 1 (0.3 to 100 nM) on quadruplex DNA at low chip loading, with
the corresponding Scatchard plot in the inset.
water ligand within the central ion channel (with possible hydrogen
bonds between the protons of H2O and the carbonyl oxygens). It is
noteworthy that cationic tetra(N-methylpyridiniumyl) porphyrins
have been among the first compounds reported to be able to target
quadruplex DNA, either as the free base H2-TMPyP13 or its
manganese analogue Mn-TMPyP.14 However, this first generation
of porphyrins did not discriminate between quadruplex and duplex
DNA12,14 owing to a strong binding to duplex DNA itself.12,14,15
The very high affinity of 1 for quadruplex DNA is associated
with a good capacity to inhibit telomerase. The cell-free enzyme-
based telomeric repeat amplification protocol (TRAP) assay showed
that 1 caused inhibition of telomerase at submicromolar concentra-
tion, with IC50 ) 580 nM.
Combining a central aromatic core and four relatively sterically
demanding flexible arms carrying cationic end groups, both a very
high affinity and an excellent selectivity for G-quadruplex DNA
over GC-rich or AT-rich duplex DNA were achieved with a
metalloporphyrin. Further studies are necessary to better understand
the binding mode of 1 and to test it in vitro on tumor cell lines and
possibly observe telomere shortening.
(6) (a) Rezler, E. M.; Seenisamy, J.; Bashyam, S.; Kim, M.-Y.; White, E.;
Wilson, W. D.; Hurley, L. H. J. Am. Chem. Soc. 2005, 127, 9439-9447.
(b) Baker, E. S.; Lee, J. T.; Sessler, J. L.; Bowers, M. T. J. Am. Chem.
Soc. 2006, 128, 2641-2648.
(7) (a) Read, M.; Harrison, R. J.; Romagnoli, B.; Tanious, F. A.; Gowan,
S. H.; Reszka, A. P.; Wilson, W. D.; Kelland, L. R.; Neidle, S. Proc.
Natl. Acad. Sci. U.S.A. 2001, 98, 4844-4849. (b) Teulade-Fichou,
M.-P.; Carrasco, C.; Guittat, L.; Bailly, C.; Alberti, P.; Mergny, J.-L.;
David, A.; Lehn, J.-M.; Wilson, W. D. J. Am. Chem. Soc. 2003, 125,
4732-4740. (c) Kaiser, M.; De Cian, A.; Sainlos, M.; Renner, C.; Mergny,
J.-L.; Teulade-Fichou, M.-P. Org. Biomol. Chem. 2006, 4, 1049-1057.
(d) Reed, J. E.; Arnal, A. A.; Neidle, S.; Vilar, R. J. Am. Chem. Soc.
2006, 128, 5992-5293. (e) Moore, M. J. B.; Schultes, C. M.; Cuesta, J.;
Cuenca, F.; Gunaratnam, M.; Tanious, F. A.; Wilson, W. D.; Neidle, S.
J. Med. Chem. 2006, 49, 582-599.
(8) (a) Shin-ya, K.; Wierzba, K.; Matsuo, K.; Ohtani, T.; Yamada, Y.; Farihata,
K.; Hayakawa, Y.; Seto, H. J. Am. Chem. Soc. 2001, 123, 1262-1263.
(b) Kim, M.-Y.; Vankayalapati, H.; Shin-ya, K.; Wierzba, K.; Hurley,
L. H. J. Am. Chem. Soc. 2002, 124, 2098-2099.
(9) Gowan, S. M.; Harrison, J. R.; Patterson, L.; Valenti, M.; Read, M. A.;
Neidle, S.; Kelland, L. R. Mol. Pharmacol. 2002, 61, 1154-1162.
(10) Schouten, J. A.; Ladame, S.; Mason, S. J.; Cooper, M. A.; Balasubrama-
nian, S. J. Am. Chem. Soc. 2003, 125, 5594-5595.
(11) (a) Isalan, M.; Patel, S. D.; Balasubramanian, S.; Choo, Y. Biochemistry
2001, 40, 830-836. (b) Patel, S. D.; Isalan, M.; Gavory, G.; Ladame, S.;
Choo, Y.; Balasubramanian, S. Biochemistry 2004, 43, 13452-13458.
(c) Ladame, S.; Schouten, J. A.; Roldan, J.; Redman, J. E.; Neidle, S.;
Balasubramanian, S. Biochemistry 2006, 45, 1393-1399.
(12) Dixon, I. M.; Lopez, F.; Este`ve, J.-P.; Tejera, A. M.; Blasco, M. A.;
Pratviel, G.; Meunier, B. ChemBioChem 2005, 6, 123-132.
(13) Wheelhouse, R. T.; Sun, D.; Han, H.; Han, F. X.; Hurley, L. H. J. Am.
Chem. Soc. 1998, 120, 3261-3262.
(14) Vialas, C.; Pratviel, G.; Meunier, B. Biochemistry 2000, 39, 9514-9522.
(15) Arnaud, P.; Zakrzewska, K.; Meunier, B. J. Comput. Chem. 2003, 24,
797-805.
Acknowledgment. M. A. Blasco’s laboratory is funded by the
MCyT (SAF2005-00277, GEN2001-4856-C13-08), by the Regional
Government of Madrid (GR/SAL/0597/2004), European Union
(TELOSENS FIGH-CT-2002-00217, INTACT LSHC-CT-2003-
506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD FI6R-
JA065591T
9
J. AM. CHEM. SOC. VOL. 129, NO. 6, 2007 1503