A Many-Faced Alkaloid: Polymorphism of (-)-Monophyllidin.

The synthesis of the alkaloid (-)-monophyllidin is described. The molecule is a hybrid of xanthoxyline and (S)-proline, accessible in one-step through a Mannich reaction. In the solid-state, defined structural arrangements with different physical properties are formed. Single crystal X-ray diffraction revealed structures of six distinct polymorphs. In the crystalline state, the alkaloid can host small polar molecules (preferably water), while the (S)-proline moiety is present in the zwitterionic state. Combined with the chelate, which is already present in the xanthoxyline substructure, an ideal disposition for multiple hydrogen bond networks evolve. Therefore, highly water-soluble polymorphs of monophyllidin can form. This structural flexibility explains the many faces of the molecule in terms of structure as well as analytical data. Furthermore, speculations about the biological role of the molecule, with regard to the manifold interactions with water, are presented.

Hybrids of salicylalkylamides and Mannich bases: control of the amide conformation by hydrogen bonding in solution and in the solid state.

3-Aminomethylation of salicylalkylamides afforded hybrids with a Mannich base. In addition, it triggered the rotation of the amide bond. The observed conformational switch is driven by strong intramolecular hydrogen bonding between the Mannich base and phenolic group. Crystal structure analysis reveals the stabilization of the hybrid molecules by double hydrogen bonding of the phenolic OH, which acts as an acceptor and donor simultaneously. The molecules contain an amide site and a Mannich base site in an orthogonal spatial arrangement. The intramolecular hydrogen bonds are persistent in a nonpolar solvent (e.g., chloroform). The conformational change can be reversed upon protection or protonation of the Mannich base nitrogen.

A novel concept for detoxification: complexation between aconitine and liquiritin in a Chinese herbal formula ('Sini Tang').

ETHNOPHARMACOLOGICAL RELEVANCE: Sini Tang (SNT) is a traditional Chinese herbal formulation consisting of three different herbs: Aconitum carmichaelii (Fuzi), Zingiber officinale (Ganjiang), and Glycyrrhiza uralensis (Gancao). For this study, we modified this mixture by adding the bark of Cinnamomum cassia (Rougui, ). Aconitum carmichaelii contains aconitine and its derivatives, all of which are highly toxic alkaloids. These compounds are commonly detoxified with pyrolytic and hydrolytic pretreatments, such as Heishunpian, which requires repeated soaking in salt water, boiling until the roots turn black, and drying in the oven. We now demonstrate that Glycyrrhiza uralensis, which is often used in Traditional Chinese Medicine for detoxification, reduces the concentration of free aconitine in decoctions by forming a complex between liquiritin and aconitine. MATERIALS AND METHODS: Aqueous extracts of SNT, each individual herb or herbal mixture, and methanolic extracts of individual herbs were tested for free aconitine by HPLC coupled with a diode array detector. A detected complex was investigated by NMR and UV/vis spectroscopy. The continuous variations method and (1)H-NMR titrations provided the complex stoichiometry and binding constant. A 2D-ROESY experiment was performed to obtain the structural details of the formed complex. RESULTS: A fast and simple HPLC method was developed to determine the amounts of aconitine and its derivatives found in herbal extracts. The Heishunpian pretreatment led to nearly complete pyrolysis and hydrolysis of the toxic compounds. However, in some batches, considerable amounts of aconitine remained. The addition of Glycyrrhiza uralensis to Aconitum carmichaelii, or liquiritin to free aconitine, led to a complexation with aconitine. The complex possessed a 1:1 stoichiometry and a binding constant of ca. 3000 L/mol to 4000 L/mol in mixtures of aqueous methanol. CONCLUSIONS: A new HPLC based method allows the concentration of toxic aconitine and other diester diterpene alkaloids in herbal extracts to be rapidly determined. This method provides a starting point for the development of routine quality control procedures. The complexation of free aconitine by adding an excess of Glycyrrhiza uralensis or free liquiritin to SNT formulations will make these formulations safer.

Structural relationships of stemona alkaloids: assessment of species-specific accumulation trends for exploiting their biological activities.

On the basis of a comparison of 42 Stemona samples, representing eight different species collected and cultivated in Thailand, species-specific accumulation trends of Stemona alkaloids were analyzed. An overview was achieved by comparative HPLC analyses of methanolic crude extracts of underground parts coupled with diode array or evaporative light scattering detectors. All major compounds were isolated and their structures elucidated by NMR and MS analyses. Protostemonine- and stichoneurine-type derivatives dominated, from which the latter characterize S. tuberosa and S. phyllantha accumulating species-specific isomers of tuberostemonine (3). The widespread S. curtisii and S. collinsiae clearly deviate by protostemonine-type derivatives dominated by stemofoline (10) and/or didehydrostemofoline (11). Further diversification within this structural type results from a mutual accumulation of derivatives with a pyrrolo- or pyridoazepine nucleus, leading to chemical variability in S. curtisii and S. aphylla.