Crystal structure of an aryl cyclohexyl nonanoid, an antiproliferative molecule isolated from the spice Myristica malabarica

An aryl cyclohexyl nonanoid, an antiproliferative compound, has been extracted from spice from M. myristica using gradient solvent elution. In the crystal, intermolecular hydroxy O—H⋯Ocarbonyl hydrogen-bonding interactions generate large 36-membered centrosymmetric cyclic dimers, which are then extended into one-dimensional ribbons along [11].

The title compound, C 21 H 26 O 5 , an aryl cyclohexyl nonanoid {systematic name: 3,5-dihydroxy-2-[9-(4-hydroxyphenyl)nonanoyl]cyclohexa-2,4-dien-1-one}, extracted from the spice plant Myristica malabarica comprises two ring components, a 4-hydroxyphenyl moiety and a 3,5-dihydroxycyclohexa-2,4dienone moiety linked by a nonanoyl chain. The molecule has an extended essentially planar conformation stabilized by an intramolecular hydroxy O-HÁ Á ÁO carbonyl hydrogen bond, giving a dihedral angle between the two ring systems of 6.37 (15) . The C, O and H atoms associated with one of the hydroxy groups of the cyclohexadienone component are disordered over two sets of sites with site occupancies of 0.6972 and 0.3028. In the crystal, hydroxy O-HÁ Á ÁO hydrogen bonds to carbonyl O-atom acceptors form large centrosymmetric R 2 2 (36) cyclic dimers, which are further extended into supramolecular onedimensional ribbon structures along [111].

Chemical context
The fruit rind of M. malabarica (family: Myristicaceae) is popularly known as Rampatri in Mumbai, India. It is used as an exotic spice in various Indian cuisines and also as a phytomedicine for the treatment of various kinds of ailments (Forrest & Heacock, 1972, and references therein). Its major pharmacological activities are credited with hepatoprotective (Morita et al., 2003), anti-carcinogenic (Patro et al., 2010;Maity et al., 2012), anti-leishmanial (Sen et al., 2007), antiulceral (Banerjee et al., 2007;Banerjee et al., 2008), antiproliferative (Manna et al., 2012(Manna et al., , 2015(Manna et al., , 2016Tyagi et al., 2014), anti-inflammatory (Maity et al., 2012), anti-quorum sensing (Chong et al., 2011) and anti-thrombotic (Olajide et al., 1999;Patro et al., 2005Patro et al., , 2010 properties and it is found as a constituent in many ayurvedic preparations such as Pasupasi. Previous phytochemical investigations of the fruit rind of M. malabarica revealed the presence of four novel diaryl nonanoids named as malabaricones A-D (Purushothaman et al., 1977) and aryl tetradecanoid . In addition, a lignan malabaricanol A and an isoflavone have been isolated from the heart wood of this plant (Purushothaman et al., 1974;Talukdar et al., 2000). A detailed phytochemical investigation of a methanol extract of the fruit rind of M. malabarica has been carried out. We have isolated a new type of molecule named as an aryl cyclohexyl nonanoid, the title compound C 21 H 26 O 5 , as a very minor constituent in addition to the reported compounds malabaricones A-D and aryl tetradecanoid. This molecule has exhibited anti-proliferative activity against various cancer cell lines such as A431, U937, MOLT-3, A549 and A2780 by using MTT and western blotting assay (unpublished result). Therefore, based on experimental results, it may be inferred that this fruit rind of M. malabarica may be used as a health promoter, a natural remedy which can be prescribed as a botanical dietary supplement to patients who are suffering from these kinds of health problems. The structure of the title compound is reported herein.

Figure 2
Centrosymmetric dimer formation in the crystal packing of the title compound, with intermolecular hydrogen bonds shown as dashed lines. registered two hits for the compounds found in M. malabarica: malabaricone-A (Bauri et al., 2006a) and malabaricone-C monohydrate (Bauri et al., 2006b), but no other examples were found resembling the title compound.

Synthesis and crystallization
The compound has been isolated as a very minor constituent from a methanol extraction of the fruit rind of M. malabarica by using CC/SiO 2 with gradient solvent elution with a binary mixture of solvent methanol and chloroform. Suitable crystals for X-ray data collection were obtained after recrystallization (Â3) from hexane:ethyl acetate (4:1), by slow evaporation at room temperature. The NMR spectroscopic analysis of the crystallized product has been interpreted as follows.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The H atoms were positioned with idealized geometry using a riding model with aromatic C-H = 0.93 Å (aromatic) or 0.97 Å (methylene). The H atoms of the OH groups were located in a difference map and were refined as riding on their parent O atoms. All H atoms were refined with isotropic displacement parameters set at 1.2 U eq of the parent atom. The atoms C4 and O2 are disordered and were refined using a split model with site-occupancy factors 0.6972:0.3028. The corresponding bond distances in the disordered groups were restrained to be equal. The reflections 0 1 14 and 0 0 7 had poor disagreement with their calculated values and were omitted from the refinement.   software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015).

Special details
Experimental. Absorption correction: CrysAlis RED (Oxford Diffraction, 2009) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. 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.