Cinnamoyl shikonin

Arnebin-1 (β,β-dimethyl acryloyl shikonin), a naturally occurring naphthoquinone from the root of the plant Arnebia nobilis, belongs to the alkanin/shikonin family (Shukla et al., 1969). The toxic effects of this compound restricted its further development as a clinically useful therapeutic agent, in spite of its wound healing, antiinflammatory, antithrombotic, antimicrobial and anticancer activities (Papageorgiou et al., 1999). This necessitated the development of numerous analogues of shikonin with greatly reduced toxicity. One such analogue is the title compound, (I), which shows a growth-inhibiting effect on prostate cancer cells (Gaddipati et al., 2000). This prompted us to undertake the present diffraction study in order to confirm the overall three-dimensional structure of (I). \sch

The conformation of (I) and the atom-numbering scheme are shown in Fig. 1. The molecule contains one naphthaquinone ring (fused ring system A/B), to which a phenyl ring (C) is attached via an ester bond, and one chiral centre (C11). Although the present study does not establish the absolute configuration of the molecule [Flack (1983) parameter 0.3 (9)], the parent shikonin has the R configuration, as determined by the chemical degradation method (Arakawa & Nakazaki, 1961). The phenyl ring C is almost parallel with the A/B ring: the interplanar angle between the two rings is 1.7 (1)°. Moreover, the phenyl ring at C19 is anti to the carbonyl group at C17 [C17—C18—C19—C20 - 175.6 (2)°].

The molecule of (I) contains two potential hydrogen-bond donors (–OH groups O5—H5 and O8—H8), which are involved in intramolecular hydrogen-bonding interactions with carbonyl groups C4═O4 and C1═O1 (Table 2) through the formation of six-membered rings (Fig. 1). The formation of such rings is preferred over intermolecular hydrogen bonding (Bilton et al. 2000). The strong intramolecular O···O distances observed in (I) are in the same range as those found in the parent naphthazarin C at 60 K (Herbstein et al. 1985).

The hydroxyl H atoms, H5 and H8, were located in a difference Fourier map, in view of the ambiguity about their positions in related naphthazarin systems (Herbstein et al. 1985). A comparison of bond lengths in (I) with those of naphthazarin C (neutron diffraction at 60 K) and other related systems (Herbstein et al., 1985, and references therein) shows that, on average, C═O is ca 0.05 Å longer (in which molecule?), while C—OH is ca 0.03 Å shorter (in which molecule?). This suggests that, in close analogy with the crystal structure of naphthazarin C, the hydroxyl H atoms are not completely localized in (I) at 100 K and that ordering will be favoured at lower temperatures, since a complete localization is only possible at 0 K.

In addition, weak hydrogen-bonding interactions of the type C—H···O are also observed (Table 2). The crystal packing (Fig. 2) further shows that the phenyl ring C stacks with the benzoquinone ring A, due to aromatic π-π interactions. The average intermolecular stacking distance and the angle between the rings, which overlap substantially in a `face-to-face' orientation as per the model proposed by Hunter (1990), are 3.3 Å and 1.1 (1)°, respectively. The benzoquinone ring being electron deficient, it can allow for a substantial face-to-face overlap with the relatively neutral phenyl ring without much π-π repulsion.