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Molecular Recognition Stacking Interactions Influence Watson-Crick vs. Hoogsteen Base-Pairing in a Model for Adenine Receptors

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3a. R = H
3b. R = tBu
La, R = H
Lb, R = t 8 ~
Scheme 2. Reaction conditions: N a H , THF, 25°C. 2 h
Molecular Recognition: Stacking Interactions
Influence Watson-Crick vs. Hoogsteen Base-Pairing
in a Model for Adenine Receptors
By Julius Rebek, Jr.,* Kevin Williams, Kevin Parris,
Pablo Ballester, and Kyu-Sung Jeong
Hydrogen bonding and aromatic stacking interactions
are the principal stabilizing forces of double-stranded nucleic acids. In recent disclosures"' from this laboratory, we
have shown how model systems can be used to assess the
individual contributions of the two types of interactions.
The new model systems consist of imides and aromatic
surfaces which converge from perpendicular directions to
provide a microenvironment complementary to adenine
derivatives (Scheme I). We have shown that l a and l b can
form from 1 and 9-ethyladenine 6a; thus the hydrogen
bonding is a composite of Watson-Crick ( l a ) and Hoogsteen ( l b ) base-pairing"I and bifurcated hydrogen bonds
can also be involved. We describe here how refinements
that influence the nature of base-pairing may be engineered into the model.
Condensation of the imide acid chloride 2 with either
@-naphthol3a or the di-tert-butyl derivativeI3' 3b gave high
yields of the corresponding esters 4a and 4b, respectively
(Scheme 2). Crystallographic
revealed the conformation shown in which a nearly perpendicular arrangement exists between the planes of the naphthalene nucleus
and the imide function in the solid state (Fig. 1 ; dihedral
angle 70" for 4a and 80" for 4b). Intermolecular stacking
is observed in the crystal structure of 4a but not in that of
4b. Apparently, the bulky tBu groups prevent this form of
self-association in 4b.
Association constants for binding of 9-ethyladenine 6a
to 4a and 4b were measured in CDCI, using N M R titration; corresponding values for 1 and the anthracene 5
have been reported."] In addition, titrations were performed with the N-methyladenine derivative 6b. Steric effects involving N 7 in such structures result in the preference of conformer 6b over 6b'JS1and thus favor base-pairing in the Hoogsteen rnode.@l
The results are presented in Table 1, with intermolecular
nuclear Overhauser enhancements (NOEs) obtained from
irradiation of the imide N-H resonance in the various
complexes;[71the estimates of Hoogsteen vs. Watson-Crick
base-pairing are calculated from the NOEs.
h y d r o g e n bonding
Scheme I
Prof. J. Rebek, Jr., K. Williams, Dr. K. Parris,
Dr. P. Ballester, Dr. K.-S. Jeong
Department of Chemistry, University of Pittsburgh
Pittsburgh, Pennsylvania 15260 (USA)
This work was supported by a grant from the National Science Founda
tion, Washington, D.C. (USA).
0 VCH Verlqsge.sellschafl mbH. D-6940 Weinheim. 1987
Fig. I . Molecular structures of 4a and 4 b 141.
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Angew. Chem. In[. Ed. Engl. 26 11987) No. 12
Table I . Association constants for the binding of 6 a and 6 b to the model
receptors 1, 4a,b, and 5, N O € values (see text), and base-pairing preferences in complexation reactions
K , , [L mol '1
NOE value [Oh]
Hoogsteen :
: 4.2
: 0.3
: 1.9
: 0.6
: 1.8
: <0.5
: 8.5
: 1.1
: 15
: 45
: 15
: 30
: <I5
: 65
: 25
The relative sizes of the NOEs observed at H2 and H8
relate to the Watson-Crick (la) and Hoogsteen (lb) basepairing, respectively. Only the extended surface of the anthracene derivative 5 favors the Watson-Crick mode (Table I , entry 7); the shorter naphthyl amide 1 or ester 4 a
show comparable amounts of both types of base-pairing
with 6a (entries 1 and 3). Binding of the N-methyl derivative 6 b to either 1 o r 4a results in about a 50% diminution
in K , since the Watson-Crick component is largely removed (entries 2 and 4). Accordingly, the NOEs observed
for H' in complexes with 6 b are much reduced compared
with HX.With the anthracene derivative 5 a larger fraction
of the binding is lost with 6 b as the Watson-Crick component is reduced.
The di-tert-butyl derivative 4 b provides an example of
remote steric effects on base-pairing. Molecular models
(CPK) indicate that interactions between the ethyl side
chain of the adenine derivative 6a and the distal tert-butyl
at C-6 of 4 b prevent close stacking in the Watson-Crick
mode but not in the Hoogsteen mode (Scheme 3, 7 vs. 8,
and Fig. 2). Experimentally, two lines of evidence support
this surmise. First, only a 30% reduction in K , is observed
for 4 b when the substituted 6 b is bound (instead of ca.
50% as observed for 1 and 4a) even though the NOEs
show most of the Watson-Crick component has been removed (entries 3 and 4). Second, 2D NOESY experiments
indicate that H8 of the adenine shows correlation only with
H ' of the naphthalene, while H 2 of the adenine shows correlation only with HS of the naphthalene; this is implicit in
structure 8. Therefore, bulky substituents on the naphthalene nucleus can orient hydrogen bonding elsewhere in the
The model receptors 1, 4a,b, and 5 can be used to
probe further details concerning multiple, weak intermole-
Fig. 2. Structure of the
complex formed between
4 b and 6a. Molecular
modeling program: MACROMODEL (W. C.
Still. Columbia University). Regions of high polarity are drawn in red
(0) and blue (N), other
regions in yellow [lo].
Angew. Chem. lnt. Ed. Engl. 26 (1987) No. 12
Scheme 3
cular forces. The esters are intrinsically less attractive to
adenine derivatives than amides (Table 1, entry 1 vs. 3 and
5) because bifurcation can be observed with the NH group
of adenine and amides"' but is not observed with the less
basic ester carbonyls of 4a,b. The enhanced binding of
4 b vs. 4a is also significant. We suggest that the tBu
groups of 4 b render its structure more polarizable and result in greater n-stacking interactions.
Finally, the model receptor and NOE techniques reveal
an additional subtlety concerning aryl-aryl interactions.
Petsko et al.['l have shown that perpendicular (edge-toface) ary-aryl interactions are common between aromatic
side chains of phenylalanine and tyrosine residues in protein structures. Such interactions combine to provide a significant means of structural stabilization. The solid-state
conformations of 4a and 4 b are in an ideal geometry for
such binding, yet irradiation of the CH, of 9-ethyladenine
6 b in contact with 4 b shows 1% enhancements in both H4
and H5 resonances of the naphthalene. Accordingly, 9 is a
contributor to the complex, and face-to-face rather than
edge-to-face interactions are indicated in these systems.
This is presumably a result of the permanent dipoles featured by these heterocyclic compounds.[''
Received: July 23, 1987;
supplemented: October 5, 1987 [Z 2373 I€]
German version: Angew. Chem. 99 (1987) 1297
[I] J. Rebek, Jr., B. Askew, P. Ballester, C. Buhr, S. Jones, D. Nemeth, K.
Williams, J . Am. Ckem. SOC.109 (1987) 5033; J. Rebek, Jr., B. Askew, P.
Ballester, C. Buhr, A. Costero, ibrd., in press.
[2] a) W. Saenger, Principles of Nucleic Acid Structure, Springer, New York
1984, Ch. 6; b) K. Hoogsteen, Acta Cryslnllogr. 16 (1963) 907.
[3] R. W. Layer, Tetrahedron Lett. 1974. 3459; D. W. Chasar, J. Org. Chem.
49 (1984) 4302. We thank Dr. Chasar for a generous sample of 3b.
[4] A dihedral angle of 60" is more common for aryl esters: R. J. Abraham,
G. H. Barnett, G. G. E. Hawkes, K. M. Smith, Tetrahedron 32 (1986)
2949. The crystallographic studies of 4 a (m.p.=214-216"C) and 4 b
(m.p.=260-263"C) will be published elsewhere. Further details of the
crystal structure investigations are available on request from the Director of the Cambridge Crystallographic Data Centre, University Chemical Laboratory, Lensfield Road, Cambridge CB2 IEW (England) on
quoting the names of the authors and the full literature citation.
[5] G. Dodin, M. Dreyfus, J:E. Dubois, J . Chem. Soc. Perkin 2 1979. 439.
[6] R. G. Lord, A. Rich, Proc. Nut. Acad. Sci. USA 57 (1967) 250; see also
Ref. [2a], Chap. 7.
[7] Enhancements were determined by integration of the difference spectra;
this technique easily permits observation of NOES a s low as 0.5% (L. D.
Hall, S. K. M. Sanders, J. Am. Chem. Soc. 102 (1980) 5703). The low
solubility of I made the NOE determination of entry 2 difficult. For a
similar application of this technique see W. H. Pirkle, T. C. Pochapsky,
ibid. 108 (1986) 5627.
[8] S. K. Burley, G . Petsko, Science (Washington) 229 (1985) 23; S. K. Burley, G. Petsko, J. Am. Ckem. SOC.108 (1986) 7995.
[9] Structures 8 and 9 represent Hoogsteen and reverse Hoogsteen conformations; Low-temperature (260 K) NOESY experiments indicate 9 is
slightly more populated than 8.
1101 J. Rebek, Jr., unpublished.
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interactions, mode, molecular, pairing, adenine, stacking, recognition, influence, base, crich, watson, hoogsteen, receptors
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