Crystal structure of 6,7-dimethoxy-1-(4-nitrophenyl)quinolin-4(1H)-one: a molecular scaffold for potential tubulin polymerization inhibitors

The single-crystal X-ray diffraction investigation of a substituted quinoline derivative, which may serve as a basis for the development of a family of cytotoxic agents, confirms the anticipated covalent structure with an unusual twisted conformation and reveals a densely packed molecular lattice.

The protein tubulin is central for maintaining normal cellular processes, and molecules interfering with the tubulin dynamics have potential in the treatment of cancerous diseases. The title compound, C 17 H 14 N 2 O 5 , was prepared as a lead compound in a project dedicated to the development of therapeutic agents binding to the colchicine binding site on tubulin, thereby interfering with the cell division in cancer cells. It holds many of the main structural characteristics for colchicine binding and has the potential for further modification and functionalization. In the title molecule, the benzene ring is inclined to the quinoline ring by 76.10 (8) . In the crystal, molecules are linked by two pairs of C-HÁ Á ÁO hydrogen bonds, forming tubular-like arrangements, propagating along the direction of the diagonals of the ab plane, and enclosing R 2 2 (26) and R 2 2 (16) ring motifs.

Chemical context
Due to the elevated rate of cell division in cancer cells, agents targeting proteins central to the mitotic process are attractive for cancer treatment (Hanahan & Weinberg, 2011). The protein tubulin polymerizes during the mitotic phase into microtubules, and this process is vital for the correct cell division (Parker et al., 2014). Based on the structures of the natural products colchicine and comberastatin A-4, a great amount of research on the synthesis and biological evaluation has been carried out (Lu et al., 2012). All these analogs bind to the colchicine binding site, and the pharmacophore and binding site is well known (Nguyen et al., 2005).
Despite large research efforts, many colchicine-binding drug candidates suffer from resistance and toxicity problems (Lu et al., 2012). Therefore, further exploration and biological evaluation of possible structures is needed. From another ISSN 2056-9890 medicinal chemistry project in our group, the title compound, (I), appeared as a side product in significant amounts. The structure was rationalized from NMR studies and confirmed by X-ray crystallography. Based on the literature and knowledge of the characteristics of molecules binding to the colchicine binding site on tubulin, it is reasonable that analogs of this structure might be potent cytotoxic agents. The reported structure can easily be further modified to improve binding affinities in correspondence with reported structureactivity studies (Lai et al., 2011;Wang et al., 2013;Patil et al., 2012). Herein, we present the synthesis and the crystal structure of the title compound, 6,7-dimethoxy-1-(4-nitrophenyl)quinolin-4(1H)-one (I).

Structural commentary
The molecular structure of (I) is depicted in Fig. 2a, where the short, double-bond nature of the C2 C3 bond [1.342 (2) Å ] is clearly visible. While the bicyclic ring systems of DAHWOE and PEBDIL (Fig. 1a) are perfectly coplanar with the C6 and C7 substituents as well as the C1 0 -atom attached to N1, this is not the case for (I); the nitrobenzene ring is inclined to the quinoline ring system by 76.10 (8) , and the torsion angle defined by atom C9, the two ring centroids and atom C1 0 is ca 167.7 ; see Fig. 2a and 2b. The more extended search fragment in Fig. 1c found 157 such torsion angles in 62 CSD entries, and in only nine compounds does this torsion angle deviate by more than ca 13.3 from planarity.

Supramolecular features
The reason for the unusual molecular conformation of (I) can be seen in Fig. 2b and 2c, where close contacts to two neighbouring molecules are apparent; these force the methoxy group and the nitrophenyl group out of the quinolinone mean plane. In the crystal, molecules are linked by two pairs of C-HÁ Á ÁO hydrogen bonds, forming tubular-like arrangements   Groom et al., 2016) identified by their six-letter reference codes. (b) Number of entries in the CSD retrieved by using various search fragments. The raw quinolin-4(1H)-one skeleton (with potential substituents on all C and N atoms) yields 759 hits (including a small number of duplicates). Three types of specifications and combinations thereof are then explored: introduction of bonds to O atoms (-OH, alkoxy or phenoxy) from C6 and C7, N1-substitution (blue, subset aromatic ring), and including only acyclic bonds from C2 and C3 atoms (red, X = any atom type, subset H only). Green and violet colours indicate the two molecules in (a). (c) Final CSD search fragment used in the conformational analysis. Dashed bonds have bond type 'any', Q is N or C, Z is 'not hydrogen', while T3 means the atom has three bonded atoms. The indicated torsion angle runs between the encircled atoms through the two ring centroids. Table 1 Hydrogen-bond geometry (Å , ).

1 Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The H atoms were included in calculated positions and treated as riding: C-H = 0.93-0.96 Å with U iso (H) = 1.5U eq (C-methyl) and 1.2U eq (C) for other H atoms.  Crystal structure of 6,7-dimethoxy-1-(4-nitrophenyl)quinolin-4(1H)-one: a molecular scaffold for potential tubulin polymerization inhibitors

6,7-Dimethoxy-1-(4-nitrophenyl)quinolin-4(1H)-one
where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.20 e Å −3 Δρ min = −0.21 e Å −3 Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.