allows the POM backbone to adopt an optimal conformation for
tight binding to complementary nucleic acids. It should therefore
be possible to introduce additional functionality, stereospecifically,
into the C79-pro-S position of the POM backbone without
markedly effecting its overall conformation and nucleic recognition
properties. As a result of this, we envisage that the physicochemical
properties of POMs could be readily modulated according to the
type of application for which they might be employed.2–4,8,9
This work was supported by the BBSRC (research grant 36/
B15998) and by the EPSRC (studentship to A.I.K). We also thank
the EPSRC National Mass Spectrometry Centre, University of
Wales, at Swansea.
Notes and references
1 (a) S. A. Benner, Science, 2004, 306, 625–626; (b) A. Eschenmoser,
Science, 1999, 284, 2118–2124; (c) P. S. Pallan, C. J. Wilds, Z. Wawrzak,
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2 (a) J. Micklefield, Curr. Med. Chem., 2001, 8, 1157–1179; (b)
D. A. Braasch and D. R. Corey, Biochemistry, 2002, 41, 4503–4510;
(c) T. Shiraishi, S. Pankratova and P. E. Nielsen, Chem. Biol., 2005, 12,
923–929; (d) G. Kolb, S. Reigadas, C. Boiziau, A. van Aerschot,
A. Arzumanov, M. J. Gait, P. Herdewijn and J.-J. Toulme,
Biochemistry, 2005, 44, 2926–2933.
Fig. 2 Idealised helical conformations of MePOMs. (A) (79R)-MePOM
in an A-type conformation with pyrrolidine ring in the N19-endo pucker
which is described by the pseudorotation phase angle (P) of 45u and d =
75u.5b (B) (79R)-MePOM in a B-type, N19-exo conformation (P = 195u, d
= 155u). (C) (79S)-MePOM in a A-type, N19-endo conformation (P = 45u,
d = 75u) conformation. In accord with X-ray crystallographic and other
data5b the c and e torsion angles are set at ca. 60u and 180u respectively.
3 (a) B. Vester and J. Wengel, Biochemistry, 2004, 43, 13233–13241; (b)
P. E. Nielsen, Curr. Opin. Biotechnol., 2001, 12, 16–20; (c) M. Petersen
and J. Wengel, Trends Biotechnol., 2003, 21, 74–81.
binds with extremely high affinity to DNA with a Tm of up to
68.0 uC with poly(dT). Such sequence dependent effects may be
due to different modes of hybridisation between the DNA and
thyminyl and adeninyl pentamers.12
4 (a) J. Wengel, Org. Biomol. Chem., 2004, 2, 277–280; (b) N. C. Seeman,
Chem. Biol., 2003, 10, 1151–1159; (c) P. S. Lukeman, A. C. Mittal and
N. C. Seeman, Chem. Commun., 2004, 1694–1695; (d) P.-S. Ng and
D. E. Bergstrom, Nano Lett., 2005, 5, 107–111.
5 (a) D. T. Hickman, P. M. King, M. A. Cooper, J. M. Slater and
J. Micklefield, Chem. Commun., 2000, 2251–2252; (b) D. T. Hickman,
T. H. S. Tan, J. Morral, P. M. King, M. A. Cooper and J. Micklefield,
Org. Biomol. Chem., 2003, 1, 3277–3292; (c) T. H. S. Tan,
D. T. Hickman, J. Morral, I. G. Beadham and J. Micklefield, Chem.
Commun., 2004, 516–517.
In order to rationalise the general trends observed here,
molecular models were generated using torsion angles derived
from a recent X-ray crystal structure of a non-methylated POM
monomer (see ESI{) and earlier energy minimised structures
derived from semi-empirical quantum mechanical calculations,
along with NMR data.5b All of this structural information is
consistent and indicates that the pyrrolidine ring of POM prefers
to adopt a trans relative configuration about the protonated
N-atom and most closely resembles the conformation of a typical
C39-endo ribose unit in an A-type RNA duplex (Fig. 2). In this
idealised conformation, the introduction of a methyl substituent
into the C79-pro-R position results in a strong 1,3-steric interaction
with the C69-amino methylene substituent. As a result of this, the
backbone torsion angle d is likely to widen to relieve the strain
driving the conformation of the pyrrolidine ring from the preferred
N19-endo to the next lowest energy N19-exo conformation,5b which
is more typical of deoxyribose in B-type DNA duplexes. On the
other hand, the introduction of a methyl substituent into the C79-
pro-S position of idealised POM backbone does not result in any
major steric interactions. Consequently, the (79S)-MePOM back-
bone is more likely to remain pre-organised in an A-type helical
conformation, which is well established to be most favourable for
formation of stable duplexes and triplexes with complementary
nucleic acids.2a
6 A. De Mesmaeker, J. Lebreton, C. Jouanno, V. Fritsch, R. M. Wolf
and S. Wendeborn, Synlett, 1997, 1287–1290.
7 (a) S. Sforza, R. Corradini, S. Ghirardi, A. Dossena and R. Marchelli,
Eur. J. Org. Chem., 2000, 2905–2913; (b) S. Sforza, G. Haaima,
R. Marchelli and P. E. Nielsen, Eur. J. Org. Chem., 1999, 197–204.
8 (a) R. Hamzavi, F. Dolle, B. Tavitian, O. Dahl and P. E. Nielsen,
Bioconjugate Chem., 2003, 14, 941–954; (b) P. Zhou, M. Wang, L. Du,
G. W. Fisher, A. Waggoner and D. H. Ly, J. Am. Chem. Soc., 2003,
125, 6878–6879.
9 (a) E. A. Englund and D. H. Appella, Org. Lett., 2005, 7, 3465–3467; (b)
P. J. Hrdlicka, B. Babu, M. D. Sorensen, N. Harrit and J. Wengel,
J. Am. Chem. Soc., 2005, 127, 13293–13299.
10 C. H. Archer, N. R. Thomas and D. Gani, Tetrahedron: Asymmetry,
1993, 4, 1141–1152.
11 M. L. Petersen and R. Vince, J. Med. Chem., 1991, 34, 2787–2797.
12 The thyminyl and adeninyl POM pentamers, described here and earlier
(see ref. 5), do not exhibit hyperchromic shifts in UV melting
experiments with non complementary homopolymers, which is
consistent with there being no non-specific base pairing. However, the
thyminyl POM pentamers could form DNA–POM2 triplexes in addition
to parallel and antiparallel duplexes with poly(dA) and d(A)20 (see ref.
5a,b). Similarly the adeninyl POM pentamers could form parallel and
antiparallel duplexes, as well as DNA2–POM triplexes with both
poly(dT) and d(T)20. The thermodynamics and kinetics for the
formation of these complexes is likely to be significantly different,
which may account for the sequence specific effects observed here. The
different modes of hybridisation will be thoroughly investigated within
our continued investigation in to the synthesis and properties of longer
mixed sequence POMs.
In summary, we have synthesised (79S)- and (79R)-MePOM
oligomers and, using UV thermal denaturation experiments and
molecular modelling, we have shown that only (79S)-methylation
1438 | Chem. Commun., 2006, 1436–1438
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