6-[3-(p-Tolylsulfonylamino)propyl]diquinothiazine1

In the title molecule {systematic name: N-[3-(diquino[3,2-b;2′,3′-e][1,4]thiazin-6-yl)propyl]-4-methylbenzenesulfonamide}, C28H24N4O2S2, the pentacyclic system is relatively planar [maximum deviation from the mean plane = 0.242 (1) Å]. The dihedral angle between two quinoline ring systems is 8.23 (2)° and that between the two halves of the 1,4-thiazine ring is 5.68 (3)°. The conformation adopted by the 3-(p-tolylsulfonylamino)propyl substituent allows for the formation of an intramolecular N—H⋯N hydrogen bond and places the benzene ring of this substituent above one of the quinoline fragments of the pentacyclic system. In the crystal, molecules are arranged via π–π stacking interactions into (0-11) layers [centroid–centroid distances = 3.981 (1)–4.320 (1) Å for the rings in the pentacyclic system and 3.645 (1) Å for the tolyl benzene rings]. In addition, molecules are involved in weak C—H⋯O, which connect the layers, and C—H⋯S hydrogen bonds. The title compound shows promising anticancer activity against renal cancer cell line UO-31.


Młodawska Comment
Heteropentacenes, mainly aza-, thia-and azathiapentacenes, are considered as polyheterocyclic donor molecules to form organic semiconductors (Anthony, 2006). We obtained heteropentacenes containing nitrogen, sulfur, oxygen and selenium via the annulation reactions (Nowak et al., 2002). One of this type was 6H-5,6,7-triaza-13-thiapentacene (II, Figure 2) which can be regarded as a new modified phenothiazine system, pentacyclic diquinothiazine, where two quinoline rings were incorporated in the ring system instead of benzene rings. This compound was further transformed by introduction of 6-alkyl, aryl, heteroaryl and aminoalkyl substituents at the thiazine nitrogen atoms. It is well known that neuroleptic phenothiazines have tricyclic dibenzothiazine ring system and the aminoalkyl substituent at the thiazine nitrogen atom in position 10. All these compounds are folded and have the central thiazine ring in a boat conformation with the aminoalkyl group in the equatorial position. 6-Substituted diquinothiazines with the aminoalkyl groups and their acyl and sulfonyl derivatives exhibit promising anticancer activities against the cell lines of 9 types of human cancer: leukemia, melanoma, non-small cell lung cancer, colon cancer, CNS cancer, ovarian cancer, renal cancer, prostate cancer and breast cancer (Pluta et al., 2010). None of phenothiazines or azaphenothiazine with the p-tolylsulfonylaminopropyl substituent have been examined by X-ray crystallography so far. The title compound (I) was obtained in a few step synthesis starting from the reactions of heteropentacenes, 6H-5,6,7-triaza-13-thiapentacene (II) and 5,7-diaza-6,13-dithiapentacene (III), with appropriate reagents (see Experimental). The structure of the title compound was assigned by spectroscopic ( 1 H NMR and MS) analysis. The diquinothiazine structure of C 2v symmetry shows a lack of the Smiles rearrangement during thia- system and shows unexpectedly U-conformation with the benzene ring placed over the pentacene system, with the dihedral angle between the C22-C26 and N6/C5A/C6A/C12A/C13A/S13 planes of 30.15 (3)°. The torsion angles including the propyl group (C15-C16-C17) show the synclinal/synclinal arrangement of the carbon chain. The torsion angles involving the sulfonamide group (C17-N18-S19-C22) show antiperiplanar/synclinal/synclinal arrangement. There is intramolecular N18-H18···N5 hydrogen bond which stabilizes the U shape of the p-tolylsulfonylaminopropyl substituent. Three intermolecular C-H···O hydrogen bonds involving the sulfonamide group and one C-H···S hydrogen bond involving the thiazine sulfur atom exist in the crystal. The molecules which are related via centers of symmetry at 0,1/2,1/2 and 1/2,1/2,1/2 stack in ribbons along the a direction via π-π interactions of the pentacyclic systems. The ribbons are further arranged into (0 -1 1) layers via another π-π interactions between benzene rings of toluene substituents ( Figure 3). Layers are glued together by the mentioned above C-H···O hydrogen bonds between aromatic carbon atoms of pentacyclic systems of one layer and sulfonamide oxygen atoms of the neighbouring layer.
The title compound shows promising anticancer activity against renal cancer cell line UO-31.

Refinement
All H atoms were treated as riding atoms in geometrically calculated positions, with d(C-H) = 0.95, 0.99 and 0.98 Å for aromatic, methylene and methyl hydrogens, respectively, except of the H atom in the N-H group of which positional parameters were refined freely, U iso (H) = kU eq (C,N), where k = 1.5 for the methyl group and k = 1.2 otherwise.  Molecular structure with displacement ellipsoids shown at the 50% probability level.

Figure 2
Related compounds.

Special details
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 F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.