Crystal structure of bergapten: a photomutagenic and photobiologically active furanocoumarin

The title molecule, bergapten, a psoralen/furanocoumarin derivative, possesses photocarcinogenic and photomutagenic activity. In the crystal, molecules are linked via C—H⋯O hydrogen bonds, forming a three-dimensional framework.


Chemical context
The title molecule, bergapten, is a linear furanocoumarin having a methoxy group in the benzene ring at position C5. This class of furano coumarins have absorption bands in the near UV region due to the presence of conjugated double bonds, and exhibit photomutagenic (Appendino, et al., 2004) and photocarcinogenic properties, binding with purine bases of DNA in living cells to yield photoadducts (Filomena et al., 2009). Based on this property, they are employed to treat numerous inflammatory skin diseases, such as atopic dermatitis, and pigment disorders like vitiligo and psoriasis by UV photodynamic therapy. In addition, due to their strong ability to absorb UV radiation, this class of molecules are utilized as photoprotective agents, to prevent the absorption of harmful UV radiation by the skin. A variety of sun-screen lotions are widely used in dermatological applications in the cosmetic and pharmaceutical industries (Chen et al., 2007(Chen et al., , 2009. In addition, the in vitro antiproliferation activity and in vivo photoxicity of the title molecule has been reported against epithelial cancer cell lines, including HL60, A431 (Conconi et al., 1998). Bergapten (5-methoxy psoralen/methoxsalen) has been used successfully in combination with UV photodynamic therapy to mange psoriasis and vitiligo; it inhibits proliferation in human hepatocellular carcinoma cell line (March et al., 1993). Experimental results revealed that its phototoxicity and photomutagenicity is exerted via a Diels-Alder reaction binding the double bond of a purine base of DNA in a living cell with the double bonds of bergapten to yield mono-and diadducts (Conforti et al., 2009).
While this is the first report of the crystal structure of the title compound, its chemical structure was determined by spectrometric and spectroscopic analysis many years ago (Howell & Robertson, 1937;Ray et al., 1937;Lin et al., 1979;Confalone & Confalone, 1983).

Structural commentary
The title compound ( Fig. 1), belongs to the psoralen class of compounds and is composed of three fused rings viz. furan, benzene and pyrone. It is an almost planar molecule with an r.m.s. deviation of 0.024 Å for the atoms of the fused ring system, O1-O2/C1-C11. The methoxy C atom, C12, is displaced from this mean plane by 0.925 (5) Å , while atoms O3 and O4 are displaced from the mean plane by 0.069 (3) and 0.035 (3) Å , respectively.

Figure 2
A view of the various C-HÁ Á ÁO hydrogen bonds (dashed lines; see Table 1 for details) in the crystal of the title compound.

Figure 3
A view along the a axis of the crystal packing of the title compound. Hydrogen bonds are drawn as dashed lines (see Table 1) and H atoms not involved in these interactions have been omitted for clarity. substituent in position 5, similar to the title compound. Two compounds closely resemble the title compound, viz. 5-hydroxypsolalen [JIXBOH; Ginderow, 1991] isolated from the bark of Citrus bergamia, and 5,8-dimethoxypsoralen [ISIMP (293 K); Gopalakrishna et al., 1977] and [ISIMP01 (120 K); Napolitano et al., 2003]. The latter was isolated from the roots and leaves of Adiscanthus fusciflorus (Rutaceae).

Synthesis and crystallization
The title compound was isolated as a colourless solid from the methanol extract of T. stictocarpum by means of column chromatography over silica gel by gradient elution with a mixture of binary solvents system hexane and ethyl acetate. It was purified by reverse phase high-pressure liquid chromatography. Colourless rod-like crystals, suitable crystals for X ray diffraction analysis, were obtained after the title compound was recrystallized three times from ethyl acetate:hexane (1:4) mixed solvents at room temperature by slow evaporation of the solvents (m.p. 469 K).

sup-1
Acta Cryst.  (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.002 Δρ max = 0.19 e Å −3 Δρ min = −0.22 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. Refinement. Refined as a 2-component twin.