Structural and thermal analyses of a hydrolysis compound of thalidomide

Thalidomide (TD) is a historically famous chiral drug. After prescription as a safe hypnotic, TD was suspected of contributing to teratogenicity, resulting in prohibition of the use of TD. TD and its derivatives, however, have attracted a renewed attention since their therapeutic effects for Hansen's disease and multiple myeloma were demonstrated. Meanwhile TD has been known to suffer from spontaneous hydrolysis with complicated pathways, leading to the production of various metabolites of TD. Therefore, we are now facing the difficulty in specifying the compounds which cause desired and/or adverse effects in the drug mechanism of TD. In a previous study, pure hydrolytic products of TD were synthesized and assayed for production-inhibitory activity of TNF-α, a kind of cytokine that induces inflammation. This study has showed that some products, especially α-(2-carboxybenzamido)glutarimide (CBG), exhibit high potency for the inhibition of TNF-α production compared to original TD. The hydrolytic products of TD thus are found to greatly attribute to the pharmacological effect of TD. For comprehending effects of the hydrolytic products, it is much significant to perform physicochemical analysis of them because their properties are deeply related to molecular stability and interaction with receptor proteins. In this study, we thus aim to investigate the physicochemical properties of CBG employing X-ray crystal structural analysis and thermal analyses. Single crystals of racemic and enantiomeric CBG were grown by solvent evaporation methods. On the crystallization, we chose alcoholic solvents such as methanol and ethanol. Surprisingly, crystals grown from the CBG solutions have indicated the same crystal structure of TD with high reproducibility. This unique result is likely to represent dehydration of CBG in non-aqueous solvents, which has not been reported so far. The detailed mechanism is under investigation.

Optical properties of chiral photomechanical salicylideneaniline crystal

Mechanical motion caused by UV/VIS radiation onto bulk materials is called a photomechanical effect. In other words, the photomechanical effect is a type of energy conversion systems. Recently, a mechanical bending of photochromic diarylethene crystals was reported, and the molecular-scale motion was found to produce the macroscale bending of the crystals (Kobatake et al., 2007). Subsequently, several photomechanical crystals have been reported to provide promising opportunities for artificial molecular machinery. The mechanism of the conversion of light energy to mechanical energy, however, has not quantitatively been understood. In photomechanical effect, microscale structural change and stress should be involved with optical properties of anisotropy and chirality; linear birefringence (LB), linear dichroism (LD), circular dichroism (CD) and optical rotatory power (ORP). CD and ORP in a chiral anisotropic crystal are extremely difficult to be measured owing exclusively to the contribution of strong linear anisotropy. The High Accuracy Universal Polarimeter generalized by our group (G-HAUP) enables us to measure LB, LD, CD, and ORP simultaneously and quantitatively (Tanaka et al., 2012). The purpose of our study is to investigate the relationship between microscale structural change or stress induced by UV/VIS radiation and the four optical properties. We synthesized chiral N-3,5-di-tert-butylsalicylidene-1-phenylethylamine photochromic crystal, as shown in Scheme 1, because the mechanism of photomechanical effect in this crystal has been revealed qualitatively by analyzing single-crystal structure under UV/VIS radiation (Koshima et al., 2013). The LB, LD, CD, and ORP spectra in the direction perpendicular to (001) were successfully measured under VIS radiation. Furthermore, LD spectrum was found to change by UV radiation in 30mW/cm². These results could contribute to an elucidation of the mechanism of photomechanical effect quantitatively.

Determination of Chirality of the Chiral Space Groups with Two-fold Screw Axis

Crystals are classified according to their symmetry operations into 230 space groups. A two-fold screw axis, 2₁, a symmetry operation, is frequently found in the crystal, especially non-centrosymmetric organic crystals. The two-fold screw axis shows a chiral character when molecules in the crystal tilt against the screw axis as shown in Figure. The crystals belonging to a chiral space group with two-fold screw axis such as a P2₁ or P2₁2₁2₁ exhibit two different types with opposite chirality. However, although the two crystals are not identical in a molecular arrangement, we cannot distinguish them with the present notation of space group. Recently, the idea of determining the handedness of two-fold screw axis have been successfully proposed using hierarchical interpretation of the crystals.(I. Hisaki, T. Sasaki et al., 2012) Nevertheless, the issue on a notation to distinguish chiral crystals with two-fold screw axis still remains unsettled as far as we know. Therefore, we attempt to propose a novel notation for the crystals belonging to chiral space groups with two-fold screw axis. We focus on the relationship between the absolute structure and optical activity of the crystals. We have selected alanine crystals, which belong to P2₁2₁2₁, as model crystals to discuss the notation. We have determined the absolute structure of the alanine crystals by X-ray diffraction and have measured their optical activity with Generalized High Accuracy Universal Polarimeter (G-HAUP).(M. Tanaka, N. Nakamura et al., 2012) G-HAUP is an apparatus that can measure simultaneously the linear birefringence, linear dichroism, circular birefringence, i.e., optical activity, and circular dichroism in any solid material. These experimental results have successfully correlated the absolute structure to the optical activity of the alanine crystals.