Oligo-ligandosides: A DNA mimetic approach to helicate formation

Article abstract of DOI:10.1039/b009855h

A novel 'ligandoside' dimer, where 2,2′-bipyridine chelators are attached to the anomeric carbons of a D-ribose-phosphate backbone, forms double stranded multinuclear complexes.

Full text of DOI:10.1039/b009855h

Oligo-ligandosides: a DNA mimetic approach to helicate formation
Haim Weizman and Yitzhak Tor*
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358, USA.
E-mail: ytor@ucsd.edu
Received (in Corvallis, OR, USA) 5th December 2000, Accepted 8th January 2001
First published as an Advance Article on the web 14th February 2001
A novel ‘ligandoside’ dimer, where 2,2A-bipyridine chelators
are attached to the anomeric carbons of a -ribose–
phosphate backbone, forms double stranded multinuclear
complexes.
phosphate triester derivative 4. Removal of the protecting
groups provides the ditopic ligand 5 (Scheme 1). The structure
of 5 was confirmed by NMR and MS.† The development of this
phosphoramidite chemistry is particularly attractive for future
solid phase synthesis of longer oligomeric strands.
D
The distinct geometry of coordination complexes has been
extensively employed for the programmed assembly of
exquisite structures.1 Among these assemblies, double stranded
multinuclear complexes known as helicates, have attracted
special attention due to their structural resemblance to the DNA
double helix and intriguing stereochemistry.2 While some
control over the stereochemical elements involved in helicate
formation (e.g. the helix chirality and the relative orientation of
non-symmetrical strands) has been achieved, controlling this
multicomponent assembly remains a challenging problem.3
Although assembling helical complexes was inspired by the
structure of the DNA double helix, none of the structural
elements inherent to DNA has been exploited in helicate design.
This is especially intriguing as both the chirality of the DNA
helix and its anti-parallel orientation are encoded in the sugar–
phosphate backbone.4 We have sought to explore if incorpora-
tion of native DNA structural elements into synthetic binders
can be employed to dictate the formation of defined complexes.
In these novel structures, ligands are attached to the anomeric
The absorption spectrum of ligand 5 shows the characteristic
p–p* absorption bands of the aromatic bpy at 242 and 287 nm.
Upon titration with Cu+ under an inert atmosphere, new bands
at 266 and 300 nm appear with three isosbestic points (Fig. 2).
An additional metal to ligand charge transfer (MLCT) band at
440 nm, characteristic of copper–bpy complex formation, also
emerges. The titration establishes a 1+1 ratio between the metal
and the ligand. This stoichiometry can be attributed either to the
formation of a mononuclear (5Cu) or a dinuclear (52Cu2)
complex. ESI mass spectrometry reveals the formation of a
mononuclear complex only (m/z 696 calcd. for 5CuNa). The
pattern and isotopic distribution exclude the possibility that this
peak represents the doubly charged complex 52Cu2.
Titration of ligand 5 with Pd2+ results in the appearance of
new absorption bands at 248 and 314 nm with two isosbestic
points (Fig. 2). The mass spectrum indicates the formation of
the mononuclear complex 5Pd (m/z 739 calcd. for 5Pd) together
with a dinuclear species (m/z 1479 calcd. for 52Pd2–H, 1500
calcd. for 52Pd2Na–H). It is difficult to establish the actual
equilibrium ratio between the various species in the mass
spectrum due to their different ionization abilities.‡
carbon of the -ribose–phosphate backbone replacing the DNA
D
nucleobases (Fig. 1). Unlike helicates where the ligands are
integrated into the helical backbone, here the ligands project
away from the backbone. Importantly, the backbone phospho-
diester groups may be considered as ‘built-in’ counter ions that
can balance the charges associated with metal complex
formation. In this contribution we present the design and
synthesis of first generation polynuclear complexes based on
this approach.
Upon titration of ligand 5 with Ag+ in MeOH, complex
formation is manifested as a shift in absorption bands to 250 and
296 nm associated with the appearance of three isosbestic points
(Fig. 2). This titration verifies the formation of a 1+1 complex
between the metal ion and the ditopic ligand (Fig. 2). The ESI
mass spectrum indicates the formation of the dinuclear complex
52Ag2 (m/z 1483 calcd. for 52Ag2H, 1505 calcd. for 52Ag2Na).
The building block for synthesizing these polytopic ligands is
a nucleoside mimic, coined ligandoside, where the heterocyclic
base is replaced by a metal-binding ligand.5,6 Our first model is
based on 2,2A-bipyridine (bpy) as a chelator (Scheme 1). A
methylene bridge is introduced between the bpy and the sugar to
allow for a more relaxed structure and dimensions similar to the
DNA double helix. The synthesis of the binding strand utilizes
the standard DNA phosphoramidite chemistry.7 The 5A-pro-
tected ligandoside 1 is converted to the phosphoramidite 2 or to
the 3A-protected acetate 3. The two components are then coupled
in the presence of 1H-tetrazole. Oxidation of the trivalent
phosphorus with iodine–water–pyridine mixture gives the
Scheme 1 Reagents and conditions: i, 2-cyanoethyl-N,N,NA,NA-tetra-
isopropylphophordiamidite, 1H-tetrazole, CH3CN, 1.5 h; ii, a. Ac2O, Py, 12
h, b. 8+2 AcOH–H2O, 1.5 h; iii, 1H-tetrazole, CH3CN, 3 h; iv, I2–THF–
H2O–Py; v, 8+2 AcOH–H2O, 1 h; vi, NH4OH, CH3CN–MeOH, 12 h.
Fig. 1 Schematic representation of a DNA mimetic metal binding dimer.
DOI: 10.1039/b009855h
Chem. Commun., 2001, 453–454
This journal is © The Royal Society of Chemistry 2001
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Fig. 3 ESI mass spectrum of the dinuclear complex 52Ag2 and its sodium
adduct. The insert shows the corresponding theoretical isotopic pattern.
Notes and references
†
Full synthetic procedures will be published elsewhere. The DMT-
protected 1 is chromatographically resolved into the a and b anomers.
Structural assignment is based on NOE experiments, where the b anomers
shows a key NOE signal between the H-1A and H-4A. Selected data for 5: 1H
NMR (400 MHz, CD3OD) d 8.61 (br s, 2H, bpy), 8.51 (br d, J = 10.0 Hz,
2H, bpy), 8.24 (br d, J = 7.6 Hz, 2H, bpy), 8.18 (br d, J = 7.6 Hz, 2H, bpy),
7.90 (m, 2H, bpy), 7.82 (m, 2H, bpy), 7.39 (m, 2H, bpy), 4.62 (m, 1H, H3Aa),
4.37 (m, 2H, H3Ab and H1Ab), 4.26 (m, 1H, H1Aa), 4.06 (m, 1H, H4Aa), 3.95
(m, 1H, H4Ab), 3.89 (m, 2H, H5Ab), 3.57 (m, 2H, H5Aa), 3.04–2.84 (m, 4H,
CH2bpy), 2.37 (m, 1H, H2Ab), 2.28 (m, 1H, H2Aa), 1.91 (m, 1H, H2Aa), 1.71
(m, 1H, H2Ab). FAB-MS calcd for C32H35N4O8P 635 found m/z 635.
‡ The mononuclear complex is singly charged and may appear as the major
component since it can be detected with no further dissociation.
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5 For the incorporation of a copper-containing ‘base-pair’ into DNA see: E.
Meggers, P. L. Holland, W. B. Tolman, F. E. Romesberg and P. G.
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Fig. 2 Uv-vis titrations of di-ligandoside monophosphate 5 in MeOH with
a. Cu(CH3CN)4BF4 in CH3CN, b. Pd(CH3CN)4(BF4)2 in CH3CN, c.
AgCF3SO3 in MeOH. Bottom: a representative curve illustrating the
formation of a 1+1 complex.
The theoretically predicted pattern and isotopic distribution
perfectly matches the experimentally observed one (Fig. 3).
These results demonstrate that threading ligands on a sugar–
phosphate backbone can lead to the formation of double
stranded structures. In the prototypical ligandoside system
described here, the formation of double stranded structures is in
competition with the formation of single stranded complexes.
This can be attributed to the flexibility of both the sugar–
phosphate backbone and the bpy–CH2 ligand. It is anticipated
that further refinement of the ligand structure (i.e. changes to the
bridging unit between the sugar and the ligand, changes to the
connection position of the bpy ring) will further increase the
tendency to form double stranded structures.
6 For the modification of DNA oligonucleotides with ligandoside building
blocks, see: H. Weizman and Y. Tor, submitted for publication.
7 M. J. Gait, Oligonucleotide Synthesis, A Practical Approach, IRL Press,
1984.
We thank the National Institutes of Health (Grant Number
GM 58447) for generous support.
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