N-(2,6-Dimeth­oxy­pyridin-3-yl)-9-methyl-9H-carbazole-3-sulfonamide

Guangzhi Shan; Zhuorong Li; Laixing Hu; Jiandong Jiang; Zongying Liu

doi:10.1107/S1600536813007460

. 2013 Mar 23;69(Pt 4):o584. doi: 10.1107/S1600536813007460

N-(2,6-Dimethoxypyridin-3-yl)-9-methyl-9H-carbazole-3-sulfonamide

Guangzhi Shan ^a, Zhuorong Li ^a, Laixing Hu ^a, Jiandong Jiang ^a, Zongying Liu ^a,^*

PMCID: PMC3629629 PMID: 23634116

Abstract

In the title compound, C₂₀H₁₉N₃O₄S, a novel tubulin ligand active against human cancer, the dihedral angle between the pyridine ring and the carbazole ring system is 42.87 (10)°. In the crystal, the molecules are held together by N—H⋯O and C—H⋯O hydrogen bonds into layers, which are assembled into a three-dimensional network via π–π stacking interactions between inversion-related pyridine rings, with centroid–centroid distances of 3.5101 (12) Å.

Related literature

For the synthesis and properties of the compound and its derivatives, see Hu et al. (2007 ▶). For tubulin as a target for anticancer activity, see Wang et al. (2008 ▶); Jackson et al. (2007 ▶); Jordan et al. (1991 ▶); Mollinedo & Gajate (2003 ▶); Wilson et al. (1999 ▶); Yvon et al. (1999 ▶). For the stability of the temperature controller used for the data collection, see Cosier & Glazer (1986 ▶). graphic file with name e-69-0o584-scheme1.jpg

Experimental

Crystal data

C₂₀H₁₉N₃O₄S
M _r = 397.45
Monoclinic,
a = 13.5078 (2) Å
b = 7.9272 (1) Å
c = 20.9276 (3) Å
β = 124.027 (1)°
V = 1857.20 (4) Å³
Z = 4
Cu Kα radiation
μ = 1.83 mm⁻¹
T = 120 K
0.45 × 0.36 × 0.32 mm

Data collection

Agilent Xcalibur (Atlas, Gemini ultra) diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.475, T _max = 0.556
11460 measured reflections
3280 independent reflections
3161 reflections with I > 2σ(I)
R _int = 0.027

Refinement

R[F ² > 2σ(F ²)] = 0.034
wR(F ²) = 0.088
S = 1.06
3280 reflections
262 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.45 e Å⁻³
Δρ_min = −0.52 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL, PLATON (Spek, 2009 ▶) and publCIF (Westrip, 2010 ▶).

Supplementary Material

Click here for additional data file.^{(30.5KB, cif)}

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536813007460/pk2469sup1.cif

e-69-0o584-sup1.cif^{(30.5KB, cif)}

Click here for additional data file.^{(160.9KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813007460/pk2469Isup2.hkl

e-69-0o584-Isup2.hkl^{(160.9KB, hkl)}

Click here for additional data file.^{(7.4KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536813007460/pk2469Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O3ⁱ	0.81 (2)	2.56 (2)	3.3387 (18)	163 (2)
C18—H18A⋯O1ⁱⁱ	0.96	2.45	3.398 (2)	170
C10—H10⋯O2ⁱⁱⁱ	0.93	2.56	3.4887 (19)	177

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

This work was supported by the National Natural Science Foundation of China (30901840) and the New Teachers’ Fund for Doctor Stations, Ministry of Education (20101106120032).

supplementary crystallographic information

Comment

Tubulin is a target for anticancer drugs (Jordan et al., 1991; Yvon et al., 1999; Wilson et al., 1999). The representative with this mode of action are the Vinca alkaloids (such as vincristine) and Taxol analogues such as paclitaxel (Jackson et al., 2007; Mollinedo et al., 2003). In this research area, N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide (IG-105, IMB-105) showed a promising anti-proliferative activity in human cancer cell lines. The title compound inhibits micro-tubule assembly by binding at the colchicine pocket and shows a potent anticancer activity in vitro and in vivo and was safe in mice (Wang et al., 2008).

The title molecule is shown in Fig. 1. In the crystal structure, the carbazole CH₃ hydrogens are disordered. The distance is 5.0286 (12) Å between the respective centroids of pyridine ring and the 6-membered ring C1\C2\C3\C4\C5\C6, and the dihedral angle between their planes is 42.87 (10) °. The intermolecular interactions that are present in the structure are N—H···O and C—H···O hydrogen bonds (Table 1) and π-π stacking interactions between inversion-related pyridine rings, with centroid-centroid distance = 3.5101 (12) Å (symmetry codes x, y, z and 2-x, -y, 1-z).

Experimental

To a solution of 3-amino-2,6-dimethoxypyridine (2.6 g, 16.8 mmol) in 45 ml dimethylfornamide at room temperature, prepared 9-methylcarbazole-3-sulfonyl chloride (5.0 g, 16.9 mmol) was added. After stirring for 5 min, triethylamine (3.6 ml, 25.6 mmol) was added, with continued stirring for 2 h. After adding ice water (50 ml), the precipitate was filtered, washed with water (20 ml) and dried, recrystallized with anhydrous ethanol, dried in vacuo to give N- (2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide as a colourless crystalline solid (5.2 g, 78%; mp: 170–172 °C).

¹H NMR (DMSO δ): 3.40 (3H, s), 3.69 (3H, s), 3.89 (3H, s), 6.28(1H, d, J = 8.0 Hz), 7.26 (1H, t, J = 7.2 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.52(1H, dd, J = 8.0, 7.2 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.70 (1H, d, J = 8.8 Hz), 7.76 (1H, d, J = 8.8 Hz), 8.21 (1H, d, J = 8.0 Hz), 8.49 (1H, s), 9.32 (1H, s).

¹³C NMR (DMSO δ): 160.2, 156.7, 142.2, 141.3, 139.3, 130.4, 126.7, 124.3, 121.6, 121.1, 120.5, 119.9, 119.8, 112.2, 109.8, 109.1, 100.6, 53.4, 52.9, 29.2.

Single crystals suitable for X-ray analysis were obtained by slow evaporation of a mixed solvent of dichloromethane and cyclohexane (3:1 v/v).