[CANCER
RESEARCH
35, 1458-1463, June 1975]
The Aqueous Solution Conformation of Tubercidin and
Tubercidin
1
Frederick E. Evans and Ramaswamy H. Sarma
Department of Chemistry, State University of New York at Albany, Albany, New York 12222
SUMMARY
./,,
The backbone of tubercidin and tubercidin 5'-phosphate
in aqueous solution has a flexible molecular framework
with
preference for 2E-gg and 2E-gg-g'g' conformations, respec
tively. The glycosyl bond is unusually flexible and no
definite preference for either anti or syn conformation could
be detected.
It is proposed
that
the
incorporation
of
tubercidin 5'-phosphate into nucleic acids will disrupt the
polymeric structure because of the high accessibility of syn
conformation, and this might be related to the reported
inhibition
H5.,
of nucleic acid and protein synthesis.
INTRODUCTION
@
Tubercidin
(Projection
I) is a powerful antibacterial
and
U
(GAUCHE)@(GAUCHE)' (G6@UcHE)'-(TRANSY (TRANs)@(64uCHE)'
antiviral agent and is used in the treatment of some forms of
cancer (2, 5, 6, 16, 29). In this paper, we provide our
findings on the aqueous solution conformation of tubercidin
and tubercidin 5'-phosphate and offer a likely conforma
tional basis, at the polynucleotide level, for the antibacterial
and antiviral properties.
g'g'
g't'
MATERIALS AND METHODS
@L
The 1H NMR2 spectra were recorded on a Varian HA
100D spectrometer
interfaced
t'g'
to a Digilab FTS-3 Fourier
transform data system. Tetramethylammonium chloride
was used as an internal reference. Tetramethylammonium
chloride (internal) = sodium 2,2-dimethyl-2-silapentane
5-sulfonate (internal) + 3.1760 ppm. The samples were
commercial preparations and were dissolved in D2O. De
tails of the experimental method have been published
elsewhere (24). The assignment of the various protons was
made from the coupling pattern, the computer simula
tion, or the effect of pH.
GAUCHE-GQJCHE [email protected]
—
TRANS
99
gt
CH2OP
VII
TRANS-GAUCHE
tg
-@
:ix
vrtr
RESULTS AND DISCUSSION
@C(8)
Analysis of the Spectra
The ‘H
NMR spectra were analyzed using the LACOON
H(I')@C(2')
C(4)
1 This
work
was
supported
by
grants
from
the
National
stitute of the NIH (CA 12462).
2 The
abbreviation
used
is:
NMR,
nuclear
magnetic
In
x
XL
ANTI
SYN
resonance.
ReceivedOctober 30, 1974;acceptedFebruary27, 1975.
1458
Cancer
Structures of various isomers.
CANCER
RESEARCH
VOL.35
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Conformation
of Tubercidin
III program, and the line shapes were generated using a
substantiated by the I .4-Hz value of the 4 bond coupling
program developed by C. H. Lee of this laboratory. The
observed and simulated spectra for the nucleoside and the
nucleotide are shown in Chart I, and the derived data are
presented in Table I. The spectra of the nucleoside and
nucleotide are illustrated in Chart 1 in such a way that one
may easily observe the perturbation due to phosphate
4J4,@ (Table
substitution
at C(5').
Particularly
noteworthy
is the pres
ence of fine structure at the 4' region of the nucleotide due to
the 4J4.@coupling.
1) (26).
The ribose ring may be treated as an equilibrium between
2E (VIII) and 3E(IX) conformations (3, 11, 15, 18, 22—24)
in aqueous solution and, based on the predicted couplings of
the “pure―
conformers (3, 19, 27, 30), the observed coupling
constants
f,'2'
or J3@
may
be used
to estimate
the
percentages of 2E (VIII) and 3E (IX) conformers. The data
in Table 1 so analyzed show that both the nucleotide and
Table 1
The Backbone Conformation
NMR parameters' for tubercidin and tubercidin 5'-phosphate
TubercidinTubercidin5-phosphateJI,_2,6.76.7J2,_3.5.35.3J3@@4.3.02.8J4
Projections II to IX represent the energy minimum
conformers about the backbone of a nucleotide (15, 21, 25,
3 1). By means of a Karplus-type
analysis
of the data in
Table 1, as described in detail elsewhere (15, 21, 25, 31),
estimates of the conformer populations (II to IX) in
aqueous solution may be attained. For determination of the
population distribution of the conformers about the
C(5')—O(S') bond (II to IV), the coupling constant sum @‘
=
J5,P
+
Jb'.P
is
used
along
with
Equation
Pg'g' is the fraction of conformers
A
(15,
21,
25,
31).
in the gauche'-gauche'
(II) orientation, and l-Pgg is the combined fraction in the
gauche'-trans'
(III)
and trans'-gauche'
(IV) orientations.
Pg'g' = (24 —
detectableNot
detectable5J,,7b0.40.5J7@$3.93.961'296.6308.4ô2'152.6157.163'120.6130.8ô4'105
(A)
The populations about the C(4')—C(S') bond (V to VII)
may be determined using Equation B (15, 21, 25, 3 1), where
@
Pgg is the gauche-gauche
coupling constant sum J45
(V) population
+ f45
and
is the
Pgg = (13 —
(B)
The coupling constant data for tubercidin and tubercidin
5'-phosphate (Table I) when manipulated as described
a The coupling
constants
and chemical
shifts are expressed
in hertz
above indicate that the nucleotide exists with an 80% (100-MHz
system),with the chemicalshifts beingdownfield from internal
gauche'-gauche' (II) population about the C(5')—O(S') tetramethylammonium chloride. The concentration for tubercidin is 0.004
bond; the population about the C(4')—C(S') bond is 60% M and that for tubercidin 5'-phosphate is 0.02 M. Both are pD 8.0, 29°.
b The
°J1.7
coupling
is not
resolved
in the
spectrum
(Chart
I).
This
gauche-gauche(V) for both the nucleotide and the nucleo
@
side at pD 8.0. The observation that the backbone of
tubercidin 5'-phosphate exists preferentially, although not
exclusively, in the g'g'-gg (II, V) conformation is further
coupling is estimated with the aid of computer simulation (Chart 1). If
Vt .- @S
not incorporated into the simulation, the C(l ‘)Hand C(7)H
resonances are significantly higher and narrower in the simulation than
they are in the actual spectrum.
Chart 1. a, ‘H
NMR spectrum of tuber
cidin at 0.003 M, pD 8.0. Chemical shifts are
expressedin hertz (100-MHz system),29°.
Number of pulses, 5000; pulse collection
time, 2 sec.b, computer simulation of a. c,
‘HNMR spectrum of tubercidin 5'-phos
phate, 0.02 M, pD 8.0, 2000 pulses, 4-sec
pulse collection time. d, simulation of c.
450
400
350
300
HERTZ
JUNE
( 100 MHz
150
tOO
50
SYSTEM)
1975
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research.
1459
F. E. Evans and R. H. Sarma
@
nucleoside have 70% 2E and 30% 3E populations in aqueous
solution at biological pH.
Although the uncertainty in the conformer population
calculations is at least ±10%, one may in a relative sense
detect net changes in populations more accurately (1 1, 15,
us here. The large upfield shift C(8)H (Chart
shows that, in a relative sense, the time-averaged conforma
tions of tubercidin and its 5'-nucleotide are quite similar. A
because,
comparison of the coupling constant data of these corn
pounds to those reported for adenosine and 5'-AMP (15, 22,
23) reveals that, for the tubercidin compounds, f,.2. is 0.5 to
when the base is orientated
syn, the repulsive
interactions between the bulky, charged phosphate group
and the pyrimidine part of the purine will force the molecule
to adopt gauche-trans and trans-gauche conformations
about the C(4')—C(S') bond (22, 23). In such syn-g/t (Chart
0.7 Hz larger, J3'4' is 0.5 to 0.7 Hz smaller, and J2.3. differs
3b) conformations,
by 0. 1 Hz as compared to adenosine and 5'-AMP. This
means that the tubercidin compounds have 5 to 10% higher
phosphate group is considerably larger than the distance
2E ribose ring populations
@
2) in going
from the phosphate dianion to a monoanion shows the
presence of anti conformation. The C(7)H chemical shift is
also effected in the anti conformation, but because of the
greater distance to the phosphate group the effect is less.
22). For the ribose ring of 5'-AMP, increases in concentra
Further examination of Chart 2 shows that the C(2)H
tion cause J, .2 to decrease and J3 . . to increase, while J2 . @,chemical shift has also been perturbed due to phosphate
and the sum J,@2. + J3.4. remain constant (15), which ionization. This contrasts with the reports on the anti
demonstrates a net increase in 3E population at the expense compounds 5'-AMP (14, 28) and 6-thiopurine riboside
of 2E (3, 11, 15, 18, 22—24).This specific behavior of the 5'-phosphate (F. E. Evans and R. H. Sarma, submitted for
coupling constants suggests that the shift in ribose ring publication) for which no effect due to phosphate ionization
population is not accompanied by changes in the dihedral on C(2)H is detected.The effecton C(2)H in tubercidin
angle of the “pure―
2E and 3E conformers (3, 11), and one 5'-phosphate is small (Chart 2) and would be expected to
should therefore be able to compute changes in population originate from syn conformers. We have reported earlier
with greater accuracy than that in the actual populations
that the effect of phosphate ionization on C(2)H chemical
(1 1, 22). Inspection of the coupling constant data in Table 1 shifts in purine nucleotides is expected to be small (14, 23)
the distance
between
C(2)H
and the
(1 1, 22) than their corresponding
adenine.counterparts. The exocyclic coupling constant sums
and @‘
are 0.5 Hz larger in the tubercidins than in the
adenosines (15, 22, 23). This is what would be expected for a
small decrease in the gg-g'g' populations for the tubercidins;
however, such a small decrease in a single coupling constant
could also be attributed to a small change in dihedral angle
of the pure conformers (II to VII).
N
w
I
z
IL&.
I
In
The Glycosyl Torsion
The orientation about the glycosyl bond in nucleosides
and nucleotides falls into 2 ranges which are called anti (X)
and syn (XI) conformation. To examine the glycosyl torsion
in tubercidin
and tubercidin
5'-phosphate,
we have used 4
different NMR methods.
Method 1. It has been shown that the perturbation
induced by phosphate ionization in 5'-@-nucleotides may be
pD
pD
used to infer information about the glycosyl torsion (9, 14,
Chart 2. The pD profiles for the C(2)H, C(8)H, and C(7)H chemical
24, 28). The pD profiles for the base protons of tubercidin shifts of tubercidin 5'-phosphate, 0.02 M, 29°,reported in hertz downfield
5'-phosphate are presented in Chart 2. The change in from internal tetramethylammonium chloride (100-MHz system). The
chemical shifts at low pD is due to ionization of the base, effect on C(2)H is not a concentration artifact. Phosphateionization has
and the change at pD values higher than 6 is due mainly to no detectableeffect on base-stackinginteractions (13, 28). In addition,
phosphate ionization, and it is this latter effect that interests nucleotides at 0.02 M exhibit very little intermolecular stacking (12, 13).
Chart 3. Perspectivedrawing of the anti (a) andsyn (b)
orientations about the glycosyl bond. In the anti conforma
tion the bond system between C(l')H and C(7)H has an
in-plane zig-zag geometry (boxed regions). In the syn
conformation,
the zig-zag pattern is destroyed, and the
C(4')-C(S') is gt.
1460
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Conformation of Tubercidin
between C(8)H and the phosphate
Table 2
group in anti-gg (Chart
Chemical shifts of the base protons
3a) conformations.
Hence,the observedlargeeffectof
phosphate
@
ionization
on the C(8)H chemical
shift and the
The chemical shifts are in hertz (100-MHz
± I Hz,
except
the
3 bases
that
arc
±2
Hz.
system) at infinite dilution
Temperature,
29°;
pD,
8.0.
small effect on the C(2)H chemical shift cannot be used to
determine the torsional preference. The only reasonable
conclusion that the pD profiles enable one to make is that
both syn and anti conformations are accessible in tubercidin
5'-phosphate. Further, ‘3C
chemical shifts of nucleotides
display pD profiles that are not parallel to such profiles
obtained from ‘H
spectra (7). This observation indicates the
uncertain nature of the use of the proton chemical shift
change caused by the dissociation of the phosphate group to
determine syn-anti populations. Further, it is not unreason
able to suggest that the flexible anti
syn equilibrium
present in tubercidin 5'-phosphate may be easily perturbed.
Changes in phosphate ionization may alter the interaction
between the phosphate and the base with a resultant change
in the time-averaged glycosyl torsion angle. Such a confor
mational shift may be producing some effect on the C(2)H
chemical shift.
Method 2. A comparison of the C(2)H and C(8)H
C(2)H in 5'-AMP
chemical shifts between the base, nucleoside, and nucleotide
Mn(II) binding study does not necessarily indicate a greater
base
torsion
preferenceAdenine509503Adenosine508516anti5-AMP―508544anti8-Bromoaden
CompoundC(2)HC(8)HC(7)HSugar
syn7-Deaza-5'-AMP499447354anti
a Other
NMR
methods
have
shown
@±
@t
syn
a
preference
for
anti
conformation
(8, 28).
b Mn
(II)
ion
binding
studies
and
theoretical
calculation
also
show
syn
conformation (23).
is a Mn(II) ion artifact and that the
provide a method of determining torsional preference in accessibility of syn conformer in metal-free tubercidin
purine nucleosides and nucleotides (14). The principle of the 5'-phosphate. This is because, in the case of 5'-AMP, the
method is that in the anti conformation the chemical shift of Mn(II) ion may simultaneously bind to the phosphate group
C(8)H will be shifted downfield due to the proximity of the and N-i of the adenine ring with the possible effect of
ribofuranose system, while the distant C(2)H will not be forcing 5'-AMP into higher populations of anti conforma
affected; in the syn conformation, the C(2)H chemical shift tion (13). Since this interaction is not possible in tubercidin
will be shifted downfield (14). Examination of the infinite
5'-phosphate (7-deaza), one might be removing this particu
dilution data for C(8)H in the 7-deaza compounds (Table 2) lar Mn(II) ion perturbation from the glycosyl conforma
indicates the presence of anti conformation in tubercidin tion. While we do not rule out this possibility, in the case of
and tubercidin 5'-phosphate. The effect on C(2)H suggests tubercidin
5'-phosphate,
2 alternative
methods
(see
the presence of syn conformer, but the effect is too small to Methods 1 and 2) also suggest syn conformation; however,
draw a definitive conclusion. A comparison of the effect on these same methods do not detect any sizable amounts of
C(2)H in the 8-bromo compounds
(Table 2), which have
syn conformation
in 5'-AMP.
been shown to be predominantly syn (23), demonstrates that
Method 4. The geometric relationship between the 5
the C(2)H chemical shift has a low sensitivity to changes in bonds connecting C(l')H and C(7)H (I) is an in-plane
glycosyl torsion ( 14, 23). The small effect on C(2)H in the “zig-zag―
in the anti conformation (Chart 3a), whereas the
tubercidins (Table 2) is compatible with the pD profiles
zig-zag is destroyed in the syn conformation (Chart 3b).
discussed Method 1.
Therefore tubercidin should possess a 5-bond coupling
Method 3. Chan and Nelson (8) have shown that the constant V,7 in the anti conformation, but no such coupling
glycosyl torsion in nucleotides may be analyzed by monitor
should be detectable in the syn conformation. Five-bond
ing the effect of added Mn(II) ion on the line widths of the couplings have been used to investigate glycosyl torsion in
base protons.
Since
Mn(II)
ion binds to the phosphate
certain pyrimidine
and triazole nucleosides (10, 17). Exami
group,therelativedistance
of thebaseprotonsissuchthat nation of the observed magnitudes of 5 bond couplings in
C(8)H will be broadened in the anti conformation and
C(2)H will be broadened in the syn conformation. Addition
of Mn(II) ion to tubercidin 5'-phosphate causes both C(2)H
and C(8)H to become broadened, which indicates the
accessibility of both the anti and syn conformations.
Both
C(2)H and C(8)H were broadened to a similar extent;
however, a detailed comparison of the C(8)H and C(2)H
linewidths is hampered since C(8)H, which is coupled to
C(7)H, will undergo relaxation decoupling (24) in the
presence of Mn(II) ion. The broadening of the base protons
various systems (4) shows that the maximum
observed value
for such a coupling through a single path is 1.5 Hz. No data
are available for a model system in which the coupling path
has the same constitution as tubercidin, i.e., H—C—N—
C=C—H.
In the tubercidins,
the observed
.J.7 of 0.4 to
0.5 Hz (Table 1) shows the presence of anti conformation.
Because one does not know the exact magnitude of such
long-range couplings in the pure anti conformation, the
5-bond coupling cannot reliably be used to infer the
magnitude of the syn population. Although anti conforma
tion is present, one cannot rule out the possibility that the
of tubercidin 5'-phosphate contrasts to that of 5'-AMP for
which C(8)H undergoes substantially more broadening than syn conformer may be the preferred glycosyl torsion.
C(2)H (8, 14).
The 4 methods used to investigate the glycosyl torsion in
One may argue that the lesser degree of broadening of the tubercidins indicate that for these compounds both syn
JUNE
1975
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1461
F. E. Evans and R. H. Sarma
and anti conformations are accessible. In the solid state (1),
in Oxy- and Deoxy-Adenyl
tubercidin
Commun.,63: 106-114,1975.
occurs with the anti conformation.
In general one
finds the preferred conformation of nucleosides and nucleo
tides in aqueous solution to be the same as that reported in
the solid state; however, there are cases in which a particular
ribose ring ( I 5), exocyclic ( 13), or glycosyl (20) conforma
tion is clearly preferred in aqueous solution, although the
crystallized form has a different conformation.
Further
more, specific evidence has been presented showing that
intermolecular
base-stacking
geometries
of nucleosides and
nucleotides in the solid state may in some cases by
considerably different from the orientations preferred in
aqueous solution (13).
Although X-ray crystallography has extracted exact
conformational parameters, because of limitations in the
technique, it has missed the most interesting dynamic
property in aqueous solution, which is the abnormal flexibil
ity about the glycosyl bond. When tubercidin
is incorpo
rated into the nucleic acid structure (2), this unusual
flexibility
would be expected
to disrupt
the biologically
functional structure. For traditional Watson-Crick type
base pairing, the purine must be in the anti conformation. It
is likely that the conformational
abnormality
is related to
Dinucleosides. Biochem. Biophys. Res.
12. Evans, F. E., and Sarma, R. H. The Tautomeric
Form of Inosine in
AqueousSolution. J. Mol. Biol., 89: 249-253, 1974.
13. Evans, F. E., and Sarma, R. H. Intermolecular Orientations of
Adenosine-5'-Monophosphatein AqueousSolution asStudiedby Fast
Fourier
Transform
‘H NMR
Spectroscopy.
Biopolymers,
13:
2117—2132,
1974.
14. Evans, F. E., and Sarma, R. H. A New Method to Determine
Sugar-BaseTorsion in Purine Nucleosidesand Nucleotides. Federa
tion EuropeanBiochem.Soc. Letters, 41: 253-255, 1974.
15. Evans, F. E., and Sarma, R. H. The Intramolecular Conformation of
Adenosine 5'-Monophosphate in Aqueous Solution as Studied by Fast
Fourier Transform ‘H
and ‘H
[31P@
Nuclear Magnetic Resonance
Spectroscopy.J. Biol. Chem., 249: 4754-4759, 1974.
16. Grage,T. B., Rochlin, F. B., Weiss,A. J., and Wilson, W. L. Clinical
Studies with Tubercidin Administered after Absorption into Human
Erythrocytes. Cancer Res.,30: 79-81, 1970.
17. Hruska, F. E. Long-rangeSpin-Spin Coupling in Pyrimidine Nucleo
sides. Can.J. Chem.,49:
2111—2118,1971.
18. Hruska, F. E. Mapping Nucleoside Conformation in Aqueous
Solution—ACorrelation of Some FuranoseStructural Parameters.
In: E. D. Bergmen and B. Pullman (eds.), The Jerusalem Symposia
on
Quantum Chemistry and Biology, Vol. 5, Conformation of Biological
Molecules and Polymers, pp. 345-360. Jerusalem: Israel Academy of
the cytotoxic properties of the tubercidins.
Sciencesand Humanities, 1973.
19. Hruska, F. E., Grey, A. A., and Smith, I. C. P. A Nuclear Magnetic
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1463
The Aqueous Solution Conformation of Tubercidin and
Tubercidin 5 ′-Phosphate
Frederick E. Evans and Ramaswamy H. Sarma
Cancer Res 1975;35:1458-1463.
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