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Interactions Between Acyclic and Cyclic Peralkylammonium Compounds and DNA.

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fen 2 (FRG) on quoting the deposition number CSD 320464,the names of
the authors, and the journal citation.
[12] SHELXTL-PLUS (VMS), Release 4.2,Siemens Analytical Instruments,
1991.
1131 A. L. Spek, PLATON 88, Program for Geometrical Analysis of Crystal
Structures, Utrecht, 1988.
[I41 E. Keller, SCHAKAL-SXB,A FORTRAN Program for the Graphic Representation of Molecular and Crystallographic Models, Freiburg, 1988.
[15] a) D. R. Armstrong, D. Barr, W. Clegg, S. M. Hodgson, R. E. Mulvey, D.
Reed, R. Snaith, D. S . Wright, J Am. Chem. Sor. 1989,111,4719-4727;
b) D. R. Armstrong, R. E. Mulvey, G. T. Walker, D. Barr, R. Snaith, W
Clegg, D. Reed, J Chem. SOC.Dalton Trans. 1988,617-628.
[16] D.R. Armstrong, D. Barr, W. Clegg, R. E. Mulvey, D. Reed, R. Snaith, K.
Wade, J Chem. SOC.Chem. Commun. 1986,869-870.
[I 71 It is probably long lithium amide ladders that precipitate from the solution
immediately after the last complexing amine molecules have been lithiated
[I,
21.
Interactions Between Acyclic and Cyclic
Peralkylammonium Compounds and DNA**
+
+
H,N-(CH,),-NH,
CI CI -
By Hans-Jorg Schneider* and Thomas Blutter
The quantification of electrostatic interactions between
DNA['' and positively charged effectors is as important for
an understanding of the biological function of biogenic
amines,['I proteins, and peptides13]as for the development of
cytostatic agents.r4I Polyamines are bound predominantly in
the strongly negatively charged larger groove of the double
helix by coulombic interactions with the ribose phosphate
groups and presumably also by formation of hydrogen
bonds with the nucle~bases.[~]
We hoped to obtain further
information on the mechanisms of molecular recognition
relevant here by systematic variation of the structure of the
polyamine - including hitherto little investigated[5d1peralkylated amines as well as amines conformationally restricted by
cyclization. Using the principle of additive increments,[6]
with which we have previously found a surprisingly uniform
coulombic interaction energy of AGES= (5 1) kJmol- for
each salt bridge (at an ionic strength of about 0) for over
50 synthetic complexes,[6b1we first analyzed known equilibrium constants1'] for complexation of the biogenic amines
1 ( K = 3 . 2 x 1 0 3 ~ - ' ) ; 2 ( K = 5 . 8 x 1 O 4 ~ - l ) and 3
( K = 2.1 x 10' M-') with DNA (Scheme 1). When the differences in the number n of the salt bridges formed between N +
(amine) and P-0-(DNA), as evident from computer-supported molecular
are taken into account, the
following values for the coulombic increment AGE, are obtained: 1 ( n = 3, AG,,, = 20) 6.7, 2 ( n = 6 , AG,,, = 27) 4.5,
and 3 (n = 7, AG,,, = 30) 4.3 (all AG values in kJ mol - '). The
average value of 5.2 kJmol-' for the interaction with DNA
lies in the same range as that of all previously analyzed salt
bridges,[61although molecular simulations[5c1indicate the
presence of two to three additional N+-H hydrogen bonds
with the nucleobases. The existence of a largely constant
bonding increment per N + group is in agreement with interactions between the DNA and protonated polyaminesr8]and
also between polylysine and polynucle~tides.[~]
The comparison of the results of measurements on peralkylated polyammonium ions (Scheme 1) with those of the
analogous compounds containing protonated nitrogen
'
[*] Prof. Dr. H.-J. Schneider, Dipl.-Chem. T. Blatter
Fachrichtung Organische Chemie der Universitat des Saarlandes
D-W-6600 Saarbriicken 11 (FRG)
['"I Host-Guestisupramolecular Chemistry, Part 33. This work was supported
by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen
Industrie. Part 32:H.-J. Schneider, I. Theis, J: Org. Chem. 1992,57, 3066.
Angew. Chem. Inl. Ed. Engl. 1992,31,No. 9
0 VCH
atoms makes it possible to estimate the contribution of the
additional hydrogen bonds present for the protonated compounds in binding to DNA. By analogy to the comparable
investigations of Stewart et al. with protonated polyamines,"] we have used the polyamine concentration level
(C,,), which leads to a 50% reduction in the fluorescence
intensity of the intercalated probe ethidium bromide, as a
measure of the interaction with the B-DNA double helix
(calf thymus). These C,, values provide, at least approximately, a measure of the various equilibrium constants for
complexation of the polyamines with the DNA.''] The affinities of the alkyluted open-chain compounds observed in this
way generally lie only a little lower than those of the correspondingly charged prolonafed compounds (compare, e.g. 4
with 3). The contribution of hydrogen bonds is therefore
almost negligibly small; this result is in agreement with observations on amide hydrogen bridges, which are completely
suppressed" 'I by protic solvents,["] especially water. This
result does not, however, exclude small differences in selec+
H3N-(CH,),-NH,-(CHJ,-NH,
CI CI Ci 2
1
+
+
+
R,N-(CHz).-NR,-(CH,).-NR,-(CH,),-NR,
+
X-
X-
X-
X-
A
A
cm
1.2
=4, R = H, X = C1
= 3 , m = 4,R = CH,, X = I
= 4,m = 2, R = CH,, X = Br
= 4,m = 6, R = CH,, X = Br
= 6, m = 2, R = CH,, X = Br
= 6, m = 6, R = CH,, X = Br
= 3: n = 3, m
4: n
5:n
6:n
7: n
8:n
+
2.1
1.5
1.8
2.2
3.0 f1.O
A?5.2
5.3
11.0
7.0
1.3
-
+
(Me,N-CH,-Ph-CH,-NMe,-),-Y
XXB
B = 9:Y = (CH,),, X = Br
10:Y = (CH,),, X = Br
11: Y = CH,-Ph-CH, X = Br
+
G o
AT
2.5
3.0
2.3
1.2
12
3.0
1.5
+
(Ph-(CH,),-NMe,-(CH,)3-NMe,)2-Y
Y = (CH,),, X
12
=
Br
(p-%),
+GcHz
H,C'
Q+
(CH,),
It
41-
N+R2-(CH2)3-NR2
17, R = CH3
R-N-(CHJ-N-R
I
I
R
C,R
R
=
CH,
c50
C = 13: n = 3
14:n = 4
15: n = 5
16: n = 6
7.2
0.27
17:
3.4
8.5
1.5
AT
2.2
5.1
1.4
3.0
Scheme 1. Structures of the polyamine derivatives 1-17 investigated. (Csovalues of these derivatives with B-DNA (calf thymus) in units of 10, M determined
by titration with ethidium bromide; changes in the melting point AT of DNA
complex in "C (with lo-, M polyammonium compound). DNA concentrations
correspond in each case to A,,, = 0.5 DNA, 0.01 SHE buffer (9.4mM NaCI.
10 mM EDTA, 2 mM HEPES (2-[4-(2-hydroxyethyI)-l-piperazino]ethanesulfonic acid), pH 7.
VerlagsgesellschaftmbH, W-6940 Weinheim, 1992
0570-0833/92/0909-l207
$3.50+ .2S/O
1207
tivity arising from additional hydrogen bridges, for example,
by a partial base-selective recognition.
Variation in the alkyl chains in the tetraammonium ions 4
to 12 leads to surprisingly small changes in the C,, values
(Scheme I), essentially in agreement with Stewart's results[*]
for protonated polyamines. Even the introduction of an
arene as spacer between the N + groups (9-12, Scheme 1)
leads to similar constants, explicable by four largely undisturbed salt bridges. This obviously is a consequence of the
small distance dependence of the coulombic potential, but
also the high flexibility of the open-chain compounds.
Macrocyclic peralkylated tetraammonium compounds
13- 17 can behave quite differently. These compounds display
an effect towards DNA that is up to 15 times higher than
that for the open-chain analogues (Scheme 1 and 2). (All the
large groove of the DNA double helix, thereby permitting
predominantly ion-pair contact between the positive +N-CH protons and the ribose phosphate oxygen atoms.
In summary, the following results have been obtained:
1 . Ionic bonding between polyamines and DNA can be described by additive increments of 5 fl kJmol-' per salt
bridge, thereby falling into the general range of numerous
inorganic and organic ion pairs. 2. Peralkylated compounds
have almost the same affinity for DNA as for example, biogenic amines, whereby the small contribution of hydrogen
bonds to the bonding with DNA is also evident here.
3. Relatively rigid azoniacyclophanes show the same or
higher affinities, although their arene units do not participate in
Received: March 2,1992 [Z 5262IE1
German version: Angew. Chem. 1992, 104, 1244
3 L-12 17 13 14 15 16
Scheme 2. AKinities of the polyammonium derivatives 3- 17 for B-DNA
W ' ) ; the minimum and maximum values for
(shown as values of 1/Cs0x
the acyclic compounds 4-12 are indicated within the columns.
azoniacyclophanes['21 13-16 employed were obtained by a
one-pot cyclization of bistosylated bis(4-aminophenyl)
methane with m,w-dibromoalkanes, and subsequent permethylation after removal of the tosyl groups.['31). For a given
number of N + groups, azoniacyclophane 14 shows by far the
highest interaction of a tetraamine with DNA that has been
seen to date. Also, in contrast to the other cyclophanes, the
change in melting point of the DNA complex is markedly
higher for 14, AT = 5.1 "C (Scheme 1).
What are the reasons for the particular high efficiency of
an azoniacyclophane? Since the host compound 16, for example, binds adenosine phosphate by enclosing the nucleobases within the cyclophane cavity with K = lo3 to
lo4 M - ' , [ ' ~ ] and a larger acridin~phane['~]
has shown itself
to be a potent intercalator['61 (by violation of the "neighbor
exclusion" principle[' 'I, according to which the inclusion of
further intercalators between neighboring base pairs is not
usually possible), an additional contribution to binding of
the cyclophane to DNA by intercalation could not be ruled
out. To examine this, we have conducted NMR and viscosity
measurements, both of which exclude intercalation. Whereas
intercalation typically causes shifts in the NMR signals of
the intercalate of 6 = - 0.7,['81for example, by ring current
effects, we have observed maximum differences of A6 = 0.02
for all aromatic protons. Moreover, the cyclophanes show
similarly small changes in viscosity (L/L,= 0.95 to 1.05)
with DNA as, for example. the open-chain spermine 3,
whereas intercalators cause considerable increases in viscosity["] (e.g. for chinacrin: L/L, =1.16). Both methods also
show the lack of intercalation for the open-chain compounds
containing aryl units (11 and 12). Electrostatic bonding
therefore remains the dominating factor, also for the azoniacyclophanes. Molecular simulation shows that the particularly effective macrocycle 14 finds sufficient space in the
1208
0 VCH
Verlagsgesellschaft mbH. W-6940 Weinheim, 1992
[I] a) W. Saenger, Principles of Nucleic Acid Structure. Springer, New York,
1984; b) G. S. Manning, Quart. Rev. Biophys. 1978, ff, 179.
[2] C. W. Tabor, H. Tabor, Annu. Rev. Biochem. 1984,53, 749.
[3] D. L. Ollis, S. W. White, Chem. Rev. 1987, 87, 981.
[4] a) Chemistry and Physics of DNA-Ligandlnteraction (Eds.: N. R. Kallenbach), Adenine Press, Guilderland, NY, USA, 1989; b) S. Neidle, Z. Abraham, Crif. Rev. Biochem. 1984, f 7, 73.
[5] a) H. R. Drew, R. E. Dickerson, J. Mol. Biol. 1981, fSf, 535; b) S. Jain, G.
Zon, M. Sundaralingam, Biochemisfry 1989, 28, 2360; c) L. Stekowski,
I
Mol. RecogD. B. Harden, R. L. Wydra, K. D. Stewart, W. D. Wilson, .
nit. 1989,2,158; d) An earlier investigation with DNA and one peralkylated steroid diamine contained no details on the contribution of hydrogen
bridge bonds: D. J. Patel, L. L. Canuel, Proe. Not. Acad. Sci. U S A 1979,
76, 24.
161 a) H.-J. Schneider, Angew. Chem. 1991,103,1419; Angew. Chem. Int. Ed.
Engl. 1992, 30, 1417; b) H.-J. Schneider, I. Theis, ibid. 1989, 101, 757 and
1989, 28, 753; c) H:J. Schneider, T. Scbiestel, P. Zimmermann, J. Am.
Chem. SOC.,in press.
[7] W. H. Braunlin, T. J. Strick, M. T. Record, Jr., Biopolymers 1982,2f, 1301.
[8] a) K. D. Stewart, Biochem. Biophys. Res. Conimun. 1988, f52, 1441;
b) K. D. Stewart, T. A. Gray, J. Phys. Org. Chem..in press, referencescited
therein. (We thank Dr. K. D. Stewart, Burroughs Welcome Co., Research
Triangle Park, USA, for a preprint.)
[9] S. A. Latt, M. A. Sober, Biochemistry 1967,6,3293;It is of interest that the
association constants (Ig K ) of polylysine with polynucleotides display a
linear increase with the length of the peptide chain, from which a value of
AG z 6 kJmol-' per lysine unit can be calculated likewise from the data
provided['] (by extrapolation to zero ionic strength).
[lo] W. J. Jorgensen, Acc. Chem. Res. 1989, 22. 184.
[ I l l Cf. H.-J. Schneider, R. K. Juneja, S. Simova, Chem. Ber. 1989, f22, 1211
and unpublished results.
[12] K. Odashima, K. Koga in Cyclophanes, Vol. 2 (Eds.: P. M. Kehn, S . M.
Rosenfeld), Academic Press, New York, 1983, 629.
[13] H.-J. Schneider, R. Busch, Chem. Ber. 1986, 119, 747.
[14] H:J. Schneider, T. Blatter, J. Am. Chem. Sac., in press.
[I51 S. C. Zimmerman, C. R. Lamberson, M. Cory, T. A. Fairly, J. Am. Chem.
Soc. 1989, f f I, 6805.
[I61 J. M. Veal, Y Li, S. C. Zimmerman, C. R. Lamberson, M. Cory, G . Zon,
W. D. Wilson, Biochemistry 1990,29,10918;see also: L. P. G. Wakelin, M.
Romanos, T. K. Chen, E. S. Canelaakis, M. J. Waring, ibid. 1978, f 7,5057.
[17] L. P. G. Wakelin, M. Romanos, T. K. Chen, D. Glaubiger, E. S. Canellakis, M. J. Waring, Biochemistry 1978, 17, 5057, and references therein.
[IS] See, for example, a) S. Chandrasekaran, S. Kusuma, D. W Boykin, W. D.
Wilson, Magn. Reson. Chem. 1986, 24, 630; b) W
. D. Wilson, F. A. Tanious, H.-J. Barton, R. L. Wydra, R. L. Jones, D. W. Boykin, L. Strekowski,
Anti-Cancer Drug Des. 1990, 5, 31.
[I91 For example W. A. Denny, Anti-Cancer Drug Des. 1989, 4, 241.
[20] The C , , measurements [8] and the melting point investigations 1221 were
carried out - as described in the cited references - with calf thymus DNA
(average molecular weight 8.9 x lo6); for the viscosity [23] and NMR [IS]
experiments solutions of DNA with 500000 < M , < 800000 (by viscometry [24]) were prepared by ultrasonic treatment. The ionic strength for the
C , , measurements was 0.01 [I71 and should, according to published literature [9,21], only lead to small reductions in the energy of complexation.
[21] a) H.-J. Schneider, R. Kramer, S. Simova, U . Schneider, J. Am. Chem. Soc.
1988, ff0,6442; b) H.-J. Schneider, I. Theis, J. Org. Chem., 1992,57, 3066.
[22] H. S. Basu, L. J. Marton, Biochem. J. 1987, 244, 243.
[23] U. Wirth, 0. Buchardt, T. Koch, P. E. Nielsen, B. Norden, J. Am. Chem.
Soc. 1988, f f 0 , 932.
[24] a) J. E. Godfrey, Bioph-vs. Chem. 1976,5,285;b) J. Eigner, P. Doty, J Mol.
B i d . 1965, f2, 549.
0S70-0833/92/0909-f208$3.50+ .2S/O
Angew. Chem. Int. Ed. Engl. 1992, 31, No. 9
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