Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270104011552/sx1139sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270104011552/sx1139Isup2.hkl |
CCDC reference: 245884
The title compound was prepared as follows. To a solution of (II) (500 mg, 1.28 mmol; Ramzaeva & Seela, 1995) in anhydrous dimethylformamide (4 ml), tetrakis(triphenylphosphine)palladium(0) [(PPh3)4Pd(0); 116 mg, 0.1 mmol], CuI (68 mg, 0.36 mmol) and triethylamine (240 µl, 1.71 mmol) were added while stirring. The sealed suspension was saturated with propyne at 273 K and stirred at room temperature for 24 h. The solvent was evaporated in vacuo, and the reaction mixture was dissolved in MeOH (2 ml), adsorbed on silica gel (2 g) and subjected to flash chromatography (silica gel 60, column 15 × 3 cm, eluent CH2Cl2—MeOH, 95:5). From the main zone, compound (I) was isolated as a colourless solid (350 mg, yield 90%). It was crystallized upon cooling from hot MeOH, yielding colourless crystals (m.p. < 483 K. UV (MeOH, nm): 236 (27800), 271 (13200). For the X-ray diffraction experiment, a single-crystal of (I) was fixed at the top of a Lindemann capillary with epoxy resin.
In the absence of significant anomalous scattering, Friedel opposites could not be used to determine the absolute structure. Refinement of the Flack parameter (Flack, 1983) led to an inconclusive value (Flack & Bernardinelli, 2000) for this parameter [-1(3)]. Therefore, Friedel equivalents were merged before the final refinement. In order to maximize the data:parameter ratio, H atoms bonded to C atoms were placed in geometrically idealized positions (C—H = 0.93–0.98 Å) and constrained to ride on their parent atoms, with Uiso(H) = 1.2Ueq(C). The hydroxy H atoms were initially placed in their difference-map positions, and were then geometrically idealized and constrained to ride on their parent O atoms, although chemically equivalent O—H bond lengths were allowed to refine while being constrained to be equal.
The incorporation of 7-deaza-2'-deoxyguanosine (Winkeler & Seela, 1983) and its 7-substituted derivatives (purine-skeleton numbering is used throughout this discussion) into oligonucleotides results in the enhancement of DNA duplex stability (Seela & Driller, 1986; Ramzaeva & Seela, 1996). Oligonucleotide triplexes are also stabilized when 7-deaza-2'-deoxyguanosine is part of the triplet motif 7-deazaguanine-guanine-cytosine (Milligan et al., 1993). Moreover, 7-deazapurine 2',3'-dideoxynucleoside triphosphates carrying 7-alkynylamino groups linked to fluorescent reporter moieties are used for DNA sequencing (Prober et al., 1987; Cocuzza, 1988; Hobbs, 1989).
The title compound, (I), is of importance because it enhances the stability of DNA-RNA duplexes (Buhr et al., 1996), as well as of duplex DNA (Seela & Shaikh, 2004). The stability increase might be caused by the increase in hydrophobicity of the major groove and/or by the increase in polarizibility of the nucleobase. Hence the potency of antisense oligonucleotides is improved (Lamm et al., 1991; Uhlmann et al., 2000). These favourable properties also find application in oligonucleotide diagnostics (Bailly & Waring, 1998). Our laboratory has shown that a propynyl group introduced into the 7-position of a `purine' base exerts a stronger stabilizing effect on DNA duplexes (He & Seela, 2002) than one in the 5-position of a pyrimidine base (Froehler et al., 1992; Wagner et al., 1993). As, in both cases, the propynyl residues protrude into the limited space of the major groove of B-DNA, it was of interest to study the crystal structure of (I) and we present the results here. \sch
Compund (I) was synthesized from the 7-iodo nucleoside, (II) (Ramzaeva & Seela, 1995), and propyne gas using the Pd-catalyst-assisted Sonogashira cross-coupling reaction (Hobbs, 1989; Robins et al., 1990), and was crystallized from MeOH. The three-dimensional structure of (I), 2-amino-7-(2-deoxy-β-D-erythro-pentofuranosyl)-5-(prop-1-ynyl) -7H-pyrrolo[2,3-d]pyrimidin-4-one (systematic numbering; IUPAC-IUB Joint Commission on Biochemical Nomenclature, 1983) is shown in Fig. 1, and selected bond distances and bond angles are presented in Table 1. In the crystalline state, the orientation of the nucleobase relative to the sugar moiety is anti (χ -117.1 (5)°), which is similar to what was found for the 8-methyl derivative of 7-deaza-2'-deoxyguanosine (Seela et al., 1997). The torsion angle χ (O4'-C1'-N9—C4) is defined by analogy with the purine system (Saenger, 1984).
The sugar ring of (I) is twisted, as shown by the torsion angles along C3'-C4'-O4'-C1' [6.7 (5)°] and C4'-O4'-C1'-C2' [-30.1 (5)°]. The pseudorotation angle P = 152.5° with an amplitude τm = 41.9°, indicating an S-type sugar pucker (2'-endo-3'-exo, 2'T3') (Rao et al., 1981), which is also the favoured conformation in solution (71%). The conformational analysis was carried out on the basis of vicinal [1H, 1H] coupling constants using the PSEUROT6.3 program (Van Wijk et al., 1999). The solid-state conformation about the C4'-C5' bond is +sc (gauche) (Saenger, 1984).
The base moiety of (I) is nearly planar, the r.m.s. deviation of the ring atoms from their calculated least-squares planes being 0.025 Å [N1 - 0.012 (4), C2 - 0.036 (4), N3 0.010 (4), C4 0.026 (4), C5 - 0.017 (5), C6 0.046 (4), C7 - 0.024 (4), C8 - 0.014 (4) and N9 0.019 (4) Å]. The O6 substituent of (I) lies 0.141 (8) Å above and the N atom of the 2-amino group -0.076 (8) Å below this plane. The linear propynyl group is in a coplanar orientation with respect to the nucleobase moiety.
The triple-bond length is 1.184 (7) Å, which corresponds to the normal length found in the Cambridge Structural Database (Version?; Allen, 2002). Apparently, the C ≡C bond is not in conjugation with the pyrrolo[2,3-d]pyrimidine heterocycle.
The structure of (I) is stabilized by several hydrogen bonds (N1—H1A···O5', N2—H2B···O4', O3'-H3'A···O6 and O5'-H5'A···O3'), leading to the formation of a multi-layered network. There are no hydrogen bonds between the layers. The bases are stacked, as are the propynyl residues (Fig. 2, Table 2). This stacking of the nucleobases might cause the extraordinary stability of DNA duplexes containing (I).
Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: SHELXTL (Sheldrick, 1997); program(s) used to solve structure: SHELXTL; program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 2003).
C14H16N4O4 | F(000) = 320 |
Mr = 304.31 | Dx = 1.430 Mg m−3 |
Monoclinic, P21 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2yb | Cell parameters from 36 reflections |
a = 4.799 (2) Å | θ = 3.0–15.1° |
b = 13.601 (3) Å | µ = 0.11 mm−1 |
c = 11.014 (3) Å | T = 293 K |
β = 100.49 (3)° | Plate, colourless |
V = 706.9 (4) Å3 | 0.6 × 0.2 × 0.1 mm |
Z = 2 |
Bruker P4 diffractometer | Rint = 0.040 |
Radiation source: fine-focus sealed tube | θmax = 28.0°, θmin = 1.9° |
Graphite monochromator | h = −1→6 |
2θ/ω scans | k = −17→1 |
2562 measured reflections | l = −14→14 |
1772 independent reflections | 3 standard reflections every 97 reflections |
1190 reflections with I > 2σ(I) | intensity decay: none |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.063 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.172 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.02 | w = 1/[σ2(Fo2) + (0.0971P)2] where P = (Fo2 + 2Fc2)/3 |
1772 reflections | (Δ/σ)max < 0.001 |
206 parameters | Δρmax = 0.32 e Å−3 |
5 restraints | Δρmin = −0.31 e Å−3 |
C14H16N4O4 | V = 706.9 (4) Å3 |
Mr = 304.31 | Z = 2 |
Monoclinic, P21 | Mo Kα radiation |
a = 4.799 (2) Å | µ = 0.11 mm−1 |
b = 13.601 (3) Å | T = 293 K |
c = 11.014 (3) Å | 0.6 × 0.2 × 0.1 mm |
β = 100.49 (3)° |
Bruker P4 diffractometer | Rint = 0.040 |
2562 measured reflections | 3 standard reflections every 97 reflections |
1772 independent reflections | intensity decay: none |
1190 reflections with I > 2σ(I) |
R[F2 > 2σ(F2)] = 0.063 | 5 restraints |
wR(F2) = 0.172 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.02 | Δρmax = 0.32 e Å−3 |
1772 reflections | Δρmin = −0.31 e Å−3 |
206 parameters |
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. |
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | ||
N1 | 0.9626 (10) | 0.5636 (4) | 0.7018 (4) | 0.0386 (11) | |
H1A | 1.0421 | 0.5327 | 0.7671 | 0.046* | |
C2 | 1.0216 (13) | 0.5327 (4) | 0.5924 (4) | 0.0365 (12) | |
N2 | 1.2035 (13) | 0.4570 (4) | 0.5966 (4) | 0.0571 (16) | |
H2A | 1.2501 | 0.4354 | 0.5297 | 0.068* | |
H2B | 1.2733 | 0.4302 | 0.6662 | 0.068* | |
N3 | 0.9137 (10) | 0.5741 (4) | 0.4852 (4) | 0.0338 (10) | |
C4 | 0.7329 (11) | 0.6477 (4) | 0.4970 (4) | 0.0291 (11) | |
C5 | 0.6472 (10) | 0.6826 (4) | 0.6027 (4) | 0.0297 (10) | |
C6 | 0.7824 (13) | 0.6422 (5) | 0.7175 (4) | 0.0403 (13) | |
O6 | 0.7554 (11) | 0.6687 (4) | 0.8226 (3) | 0.0591 (13) | |
C7 | 0.4432 (11) | 0.7595 (4) | 0.5667 (4) | 0.0307 (11) | |
C8 | 0.4132 (11) | 0.7660 (4) | 0.4414 (4) | 0.0302 (10) | |
H8A | 0.2923 | 0.8095 | 0.3922 | 0.036* | |
N9 | 0.5862 (9) | 0.6995 (3) | 0.3982 (3) | 0.0287 (9) | |
C71 | 0.2865 (12) | 0.8148 (4) | 0.6423 (4) | 0.0357 (12) | |
C72 | 0.1500 (12) | 0.8603 (5) | 0.7020 (5) | 0.0404 (13) | |
C73 | −0.0309 (15) | 0.9163 (6) | 0.7701 (5) | 0.0543 (17) | |
H73A | −0.1637 | 0.9545 | 0.7132 | 0.081* | |
H73B | 0.0840 | 0.9594 | 0.8275 | 0.081* | |
H73C | −0.1320 | 0.8719 | 0.8141 | 0.081* | |
C1' | 0.6218 (12) | 0.6851 (4) | 0.2718 (4) | 0.0297 (10) | |
H1'A | 0.7581 | 0.6320 | 0.2683 | 0.036* | |
C2' | 0.3541 (12) | 0.6649 (5) | 0.1805 (4) | 0.0353 (12) | |
H2'A | 0.1992 | 0.7061 | 0.1958 | 0.042* | |
H2'B | 0.2988 | 0.5964 | 0.1821 | 0.042* | |
C3' | 0.4441 (11) | 0.6913 (4) | 0.0593 (4) | 0.0314 (11) | |
H3'B | 0.2813 | 0.7091 | −0.0043 | 0.038* | |
O3' | 0.5936 (10) | 0.6086 (3) | 0.0229 (3) | 0.0486 (12) | |
H3'A | 0.625 (14) | 0.619 (2) | −0.047 (3) | 0.073* | |
C4' | 0.6420 (11) | 0.7786 (4) | 0.0949 (4) | 0.0286 (10) | |
H4'A | 0.8096 | 0.7706 | 0.0566 | 0.034* | |
O4' | 0.7296 (7) | 0.7758 (3) | 0.2284 (2) | 0.0309 (8) | |
C5' | 0.5068 (15) | 0.8766 (3) | 0.0568 (5) | 0.0476 (16) | |
H5'B | 0.4417 | 0.8776 | −0.0319 | 0.057* | |
H5'C | 0.3440 | 0.8863 | 0.0963 | 0.057* | |
O5' | 0.7047 (11) | 0.9532 (3) | 0.0912 (4) | 0.0588 (14) | |
H5'A | 0.654 (9) | 1.0027 (19) | 0.051 (5) | 0.088* |
U11 | U22 | U33 | U12 | U13 | U23 | |
N1 | 0.055 (3) | 0.037 (3) | 0.0213 (17) | 0.003 (2) | 0.0012 (18) | 0.0089 (17) |
C2 | 0.054 (3) | 0.023 (2) | 0.032 (2) | 0.001 (3) | 0.008 (2) | 0.0038 (19) |
N2 | 0.087 (4) | 0.040 (3) | 0.042 (3) | 0.024 (3) | 0.007 (3) | 0.010 (2) |
N3 | 0.052 (3) | 0.023 (2) | 0.0263 (18) | 0.009 (2) | 0.0051 (18) | 0.0022 (15) |
C4 | 0.039 (3) | 0.027 (2) | 0.0216 (19) | 0.001 (2) | 0.0046 (18) | 0.0041 (17) |
C5 | 0.036 (3) | 0.030 (2) | 0.024 (2) | −0.003 (2) | 0.0070 (18) | −0.0002 (18) |
C6 | 0.057 (4) | 0.039 (3) | 0.027 (2) | 0.001 (3) | 0.016 (2) | 0.004 (2) |
O6 | 0.098 (4) | 0.059 (3) | 0.0237 (17) | 0.009 (3) | 0.020 (2) | 0.0004 (18) |
C7 | 0.038 (3) | 0.027 (2) | 0.030 (2) | −0.002 (2) | 0.0142 (19) | 0.000 (2) |
C8 | 0.039 (3) | 0.024 (2) | 0.029 (2) | 0.005 (2) | 0.0083 (19) | 0.0004 (19) |
N9 | 0.040 (2) | 0.027 (2) | 0.0208 (17) | 0.007 (2) | 0.0088 (16) | 0.0025 (15) |
C71 | 0.043 (3) | 0.034 (3) | 0.032 (2) | −0.004 (3) | 0.010 (2) | −0.002 (2) |
C72 | 0.047 (3) | 0.042 (3) | 0.033 (2) | 0.004 (3) | 0.008 (2) | −0.005 (2) |
C73 | 0.054 (4) | 0.063 (4) | 0.047 (3) | 0.011 (4) | 0.013 (3) | −0.015 (3) |
C1' | 0.049 (3) | 0.019 (2) | 0.023 (2) | −0.001 (2) | 0.0139 (19) | 0.0039 (16) |
C2' | 0.042 (3) | 0.037 (3) | 0.029 (2) | −0.009 (3) | 0.012 (2) | −0.003 (2) |
C3' | 0.042 (3) | 0.028 (2) | 0.0222 (19) | 0.003 (2) | 0.0001 (19) | −0.0028 (17) |
O3' | 0.094 (4) | 0.0207 (17) | 0.0353 (19) | −0.006 (2) | 0.023 (2) | −0.0048 (15) |
C4' | 0.043 (3) | 0.019 (2) | 0.0210 (18) | 0.001 (2) | −0.0005 (18) | 0.0031 (17) |
O4' | 0.048 (2) | 0.0229 (16) | 0.0193 (13) | −0.0086 (17) | −0.0011 (13) | 0.0007 (12) |
C5' | 0.070 (4) | 0.022 (2) | 0.043 (3) | 0.007 (3) | −0.009 (3) | 0.007 (2) |
O5' | 0.094 (4) | 0.0190 (17) | 0.050 (2) | −0.006 (2) | −0.022 (2) | 0.0089 (17) |
N1—C2 | 1.355 (7) | C73—H73A | 0.9600 |
N1—C6 | 1.405 (7) | C73—H73B | 0.9600 |
N1—H1A | 0.8600 | C73—H73C | 0.9600 |
C2—N3 | 1.325 (6) | C1'—O4' | 1.452 (6) |
C2—N2 | 1.345 (8) | C1'—C2' | 1.506 (7) |
N2—H2A | 0.8600 | C1'—H1'A | 0.9800 |
N2—H2B | 0.8600 | C2'—C3' | 1.518 (6) |
N3—C4 | 1.346 (6) | C2'—H2'A | 0.9700 |
C4—N9 | 1.377 (6) | C2'—H2'B | 0.9700 |
C4—C5 | 1.387 (6) | C3'—O3' | 1.430 (6) |
C5—C6 | 1.422 (7) | C3'—C4' | 1.527 (7) |
C5—C7 | 1.438 (7) | C3'—H3'B | 0.9800 |
C6—O6 | 1.242 (6) | O3'—H3'A | 0.82 (4) |
C7—C8 | 1.364 (6) | C4'—O4' | 1.454 (5) |
C7—C71 | 1.433 (7) | C4'—C5' | 1.508 (7) |
C8—N9 | 1.371 (6) | C4'—H4'A | 0.9800 |
C8—H8A | 0.9300 | C5'—O5' | 1.414 (7) |
N9—C1' | 1.447 (5) | C5'—H5'B | 0.9700 |
C71—C72 | 1.184 (8) | C5'—H5'C | 0.9700 |
C72—C73 | 1.461 (8) | O5'—H5'A | 0.82 (4) |
C2—N1—C6 | 125.4 (4) | H73B—C73—H73C | 109.5 |
C2—N1—H1A | 117.3 | N9—C1'—O4' | 108.3 (4) |
C6—N1—H1A | 117.3 | N9—C1'—C2' | 115.6 (4) |
N3—C2—N2 | 120.2 (5) | O4'—C1'—C2' | 104.3 (4) |
N3—C2—N1 | 123.3 (5) | N9—C1'—H1'A | 109.5 |
N2—C2—N1 | 116.5 (5) | O4'—C1'—H1'A | 109.5 |
C2—N2—H2A | 120.0 | C2'—C1'—H1'A | 109.5 |
C2—N2—H2B | 120.0 | C1'—C2'—C3' | 101.5 (4) |
H2A—N2—H2B | 120.0 | C1'—C2'—H2'A | 111.5 |
C2—N3—C4 | 112.6 (4) | C3'—C2'—H2'A | 111.5 |
N3—C4—N9 | 123.3 (4) | C1'—C2'—H2'B | 111.5 |
N3—C4—C5 | 129.1 (4) | C3'—C2'—H2'B | 111.5 |
N9—C4—C5 | 107.5 (4) | H2'A—C2'—H2'B | 109.3 |
C4—C5—C6 | 117.2 (5) | O3'—C3'—C2' | 107.4 (4) |
C4—C5—C7 | 108.0 (4) | O3'—C3'—C4' | 111.3 (4) |
C6—C5—C7 | 134.7 (4) | C2'—C3'—C4' | 102.8 (4) |
O6—C6—N1 | 120.4 (5) | O3'—C3'—H3'B | 111.7 |
O6—C6—C5 | 127.5 (6) | C2'—C3'—H3'B | 111.7 |
N1—C6—C5 | 112.1 (4) | C4'—C3'—H3'B | 111.7 |
C8—C7—C71 | 125.7 (5) | C3'—O3'—H3'A | 108 (3) |
C8—C7—C5 | 105.5 (4) | O4'—C4'—C5' | 109.6 (4) |
C71—C7—C5 | 128.6 (4) | O4'—C4'—C3' | 106.9 (4) |
C7—C8—N9 | 110.4 (4) | C5'—C4'—C3' | 113.6 (4) |
C7—C8—H8A | 124.8 | O4'—C4'—H4'A | 108.9 |
N9—C8—H8A | 124.8 | C5'—C4'—H4'A | 108.9 |
C8—N9—C4 | 108.6 (4) | C3'—C4'—H4'A | 108.9 |
C8—N9—C1' | 127.5 (4) | C1'—O4'—C4' | 107.5 (3) |
C4—N9—C1' | 123.9 (4) | O5'—C5'—C4' | 110.1 (5) |
C72—C71—C7 | 178.0 (6) | O5'—C5'—H5'B | 109.7 |
C71—C72—C73 | 177.0 (6) | C4'—C5'—H5'B | 109.7 |
C72—C73—H73A | 109.5 | O5'—C5'—H5'C | 109.7 |
C72—C73—H73B | 109.5 | C4'—C5'—H5'C | 109.7 |
H73A—C73—H73B | 109.5 | H5'B—C5'—H5'C | 108.2 |
C72—C73—H73C | 109.5 | C5'—O5'—H5'A | 110 (3) |
H73A—C73—H73C | 109.5 | ||
C6—N1—C2—N3 | 0.2 (9) | C7—C8—N9—C1' | −178.3 (5) |
C6—N1—C2—N2 | 178.9 (5) | N3—C4—N9—C8 | 177.6 (4) |
N2—C2—N3—C4 | 179.1 (5) | C5—C4—N9—C8 | 0.3 (6) |
N1—C2—N3—C4 | −2.1 (8) | N3—C4—N9—C1' | −3.9 (7) |
C2—N3—C4—N9 | −177.6 (5) | C5—C4—N9—C1' | 178.9 (4) |
C2—N3—C4—C5 | −1.0 (8) | C8—N9—C1'—O4' | 61.2 (7) |
N3—C4—C5—C6 | 5.8 (8) | C4—N9—C1'—O4' | −117.1 (5) |
N9—C4—C5—C6 | −177.2 (5) | C8—N9—C1'—C2' | −55.3 (7) |
N3—C4—C5—C7 | −177.8 (5) | C4—N9—C1'—C2' | 126.4 (5) |
N9—C4—C5—C7 | −0.7 (6) | N9—C1'—C2'—C3' | 159.9 (4) |
C2—N1—C6—O6 | −175.6 (6) | O4'—C1'—C2'—C3' | 41.2 (5) |
C2—N1—C6—C5 | 4.5 (8) | C1'—C2'—C3'—O3' | 81.5 (5) |
C4—C5—C6—O6 | 173.3 (6) | C1'—C2'—C3'—C4' | −36.0 (5) |
C7—C5—C6—O6 | −1.9 (11) | O3'—C3'—C4'—O4' | −95.8 (4) |
C4—C5—C6—N1 | −6.8 (7) | C2'—C3'—C4'—O4' | 18.9 (5) |
C7—C5—C6—N1 | 178.0 (5) | O3'—C3'—C4'—C5' | 143.2 (5) |
C4—C5—C7—C8 | 0.9 (5) | C2'—C3'—C4'—C5' | −102.1 (5) |
C6—C5—C7—C8 | 176.4 (6) | N9—C1'—O4'—C4' | −153.7 (4) |
C4—C5—C7—C71 | 177.2 (5) | C2'—C1'—O4'—C4' | −30.1 (5) |
C6—C5—C7—C71 | −7.3 (10) | C5'—C4'—O4'—C1' | 130.3 (5) |
C71—C7—C8—N9 | −177.1 (5) | C3'—C4'—O4'—C1' | 6.7 (5) |
C5—C7—C8—N9 | −0.7 (5) | O4'—C4'—C5'—O5' | 61.5 (6) |
C7—C8—N9—C4 | 0.2 (6) | C3'—C4'—C5'—O5' | −179.0 (5) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1A···O5′i | 0.86 | 2.10 | 2.946 (6) | 170 |
N2—H2B···O4′i | 0.86 | 2.40 | 3.109 (6) | 140 |
O3′—H3′A···O6ii | 0.82 (4) | 1.80 (2) | 2.600 (6) | 164 (7) |
O5′—H5′A···O3′iii | 0.82 (4) | 1.95 (2) | 2.727 (6) | 159 (7) |
Symmetry codes: (i) −x+2, y−1/2, −z+1; (ii) x, y, z−1; (iii) −x+1, y+1/2, −z. |
Experimental details
Crystal data | |
Chemical formula | C14H16N4O4 |
Mr | 304.31 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 293 |
a, b, c (Å) | 4.799 (2), 13.601 (3), 11.014 (3) |
β (°) | 100.49 (3) |
V (Å3) | 706.9 (4) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.11 |
Crystal size (mm) | 0.6 × 0.2 × 0.1 |
Data collection | |
Diffractometer | Bruker P4 |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 2562, 1772, 1190 |
Rint | 0.040 |
(sin θ/λ)max (Å−1) | 0.660 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.063, 0.172, 1.02 |
No. of reflections | 1772 |
No. of parameters | 206 |
No. of restraints | 5 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.32, −0.31 |
Computer programs: XSCANS (Siemens, 1996), XSCANS, SHELXTL (Sheldrick, 1997), SHELXTL and PLATON (Spek, 2003).
C7—C71 | 1.433 (7) | C72—C73 | 1.461 (8) |
N9—C1' | 1.447 (5) | C1'—O4' | 1.452 (6) |
C71—C72 | 1.184 (8) | C4'—O4' | 1.454 (5) |
N3—C4—N9 | 123.3 (4) | C71—C72—C73 | 177.0 (6) |
N9—C4—C5 | 107.5 (4) | N9—C1'—O4' | 108.3 (4) |
C8—C7—C71 | 125.7 (5) | N9—C1'—C2' | 115.6 (4) |
C71—C7—C5 | 128.6 (4) | O4'—C4'—C5' | 109.6 (4) |
C8—N9—C4 | 108.6 (4) | O4'—C4'—C3' | 106.9 (4) |
C8—N9—C1' | 127.5 (4) | C5'—C4'—C3' | 113.6 (4) |
C4—N9—C1' | 123.9 (4) | C1'—O4'—C4' | 107.5 (3) |
C72—C71—C7 | 178.0 (6) | O5'—C5'—C4' | 110.1 (5) |
C2—N3—C4—N9 | −177.6 (5) | C4—N9—C1'—C2' | 126.4 (5) |
C4—C5—C7—C71 | 177.2 (5) | N9—C1'—C2'—C3' | 159.9 (4) |
C6—C5—C7—C71 | −7.3 (10) | C1'—C2'—C3'—C4' | −36.0 (5) |
C7—C8—N9—C1' | −178.3 (5) | C2'—C3'—C4'—O4' | 18.9 (5) |
N3—C4—N9—C1' | −3.9 (7) | C2'—C3'—C4'—C5' | −102.1 (5) |
C5—C4—N9—C1' | 178.9 (4) | N9—C1'—O4'—C4' | −153.7 (4) |
C8—N9—C1'—O4' | 61.2 (7) | C2'—C1'—O4'—C4' | −30.1 (5) |
C4—N9—C1'—O4' | −117.1 (5) | C5'—C4'—O4'—C1' | 130.3 (5) |
C8—N9—C1'—C2' | −55.3 (7) | C3'—C4'—O4'—C1' | 6.7 (5) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1A···O5'i | 0.86 | 2.10 | 2.946 (6) | 170 |
N2—H2B···O4'i | 0.86 | 2.40 | 3.109 (6) | 140 |
O3'—H3'A···O6ii | 0.82 (4) | 1.80 (2) | 2.600 (6) | 164 (7) |
O5'—H5'A···O3'iii | 0.82 (4) | 1.95 (2) | 2.727 (6) | 159 (7) |
Symmetry codes: (i) −x+2, y−1/2, −z+1; (ii) x, y, z−1; (iii) −x+1, y+1/2, −z. |
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The incorporation of 7-deaza-2'-deoxyguanosine (Winkeler & Seela, 1983) and its 7-substituted derivatives (purine-skeleton numbering is used throughout this discussion) into oligonucleotides results in the enhancement of DNA duplex stability (Seela & Driller, 1986; Ramzaeva & Seela, 1996). Oligonucleotide triplexes are also stabilized when 7-deaza-2'-deoxyguanosine is part of the triplet motif 7-deazaguanine-guanine-cytosine (Milligan et al., 1993). Moreover, 7-deazapurine 2',3'-dideoxynucleoside triphosphates carrying 7-alkynylamino groups linked to fluorescent reporter moieties are used for DNA sequencing (Prober et al., 1987; Cocuzza, 1988; Hobbs, 1989).
The title compound, (I), is of importance because it enhances the stability of DNA-RNA duplexes (Buhr et al., 1996), as well as of duplex DNA (Seela & Shaikh, 2004). The stability increase might be caused by the increase in hydrophobicity of the major groove and/or by the increase in polarizibility of the nucleobase. Hence the potency of antisense oligonucleotides is improved (Lamm et al., 1991; Uhlmann et al., 2000). These favourable properties also find application in oligonucleotide diagnostics (Bailly & Waring, 1998). Our laboratory has shown that a propynyl group introduced into the 7-position of a `purine' base exerts a stronger stabilizing effect on DNA duplexes (He & Seela, 2002) than one in the 5-position of a pyrimidine base (Froehler et al., 1992; Wagner et al., 1993). As, in both cases, the propynyl residues protrude into the limited space of the major groove of B-DNA, it was of interest to study the crystal structure of (I) and we present the results here. \sch
Compund (I) was synthesized from the 7-iodo nucleoside, (II) (Ramzaeva & Seela, 1995), and propyne gas using the Pd-catalyst-assisted Sonogashira cross-coupling reaction (Hobbs, 1989; Robins et al., 1990), and was crystallized from MeOH. The three-dimensional structure of (I), 2-amino-7-(2-deoxy-β-D-erythro-pentofuranosyl)-5-(prop-1-ynyl) -7H-pyrrolo[2,3-d]pyrimidin-4-one (systematic numbering; IUPAC-IUB Joint Commission on Biochemical Nomenclature, 1983) is shown in Fig. 1, and selected bond distances and bond angles are presented in Table 1. In the crystalline state, the orientation of the nucleobase relative to the sugar moiety is anti (χ -117.1 (5)°), which is similar to what was found for the 8-methyl derivative of 7-deaza-2'-deoxyguanosine (Seela et al., 1997). The torsion angle χ (O4'-C1'-N9—C4) is defined by analogy with the purine system (Saenger, 1984).
The sugar ring of (I) is twisted, as shown by the torsion angles along C3'-C4'-O4'-C1' [6.7 (5)°] and C4'-O4'-C1'-C2' [-30.1 (5)°]. The pseudorotation angle P = 152.5° with an amplitude τm = 41.9°, indicating an S-type sugar pucker (2'-endo-3'-exo, 2'T3') (Rao et al., 1981), which is also the favoured conformation in solution (71%). The conformational analysis was carried out on the basis of vicinal [1H, 1H] coupling constants using the PSEUROT6.3 program (Van Wijk et al., 1999). The solid-state conformation about the C4'-C5' bond is +sc (gauche) (Saenger, 1984).
The base moiety of (I) is nearly planar, the r.m.s. deviation of the ring atoms from their calculated least-squares planes being 0.025 Å [N1 - 0.012 (4), C2 - 0.036 (4), N3 0.010 (4), C4 0.026 (4), C5 - 0.017 (5), C6 0.046 (4), C7 - 0.024 (4), C8 - 0.014 (4) and N9 0.019 (4) Å]. The O6 substituent of (I) lies 0.141 (8) Å above and the N atom of the 2-amino group -0.076 (8) Å below this plane. The linear propynyl group is in a coplanar orientation with respect to the nucleobase moiety.
The triple-bond length is 1.184 (7) Å, which corresponds to the normal length found in the Cambridge Structural Database (Version?; Allen, 2002). Apparently, the C ≡C bond is not in conjugation with the pyrrolo[2,3-d]pyrimidine heterocycle.
The structure of (I) is stabilized by several hydrogen bonds (N1—H1A···O5', N2—H2B···O4', O3'-H3'A···O6 and O5'-H5'A···O3'), leading to the formation of a multi-layered network. There are no hydrogen bonds between the layers. The bases are stacked, as are the propynyl residues (Fig. 2, Table 2). This stacking of the nucleobases might cause the extraordinary stability of DNA duplexes containing (I).