Chemoenzymatic total synthesis of rotigotine via IRED-catalyzed reductive amination.

A short and chemoenzymatic synthesis of rotigotine using an IR-36-M5 mutant is reported. Focusing on the residues that directly contact the 2-tetralone moiety, we applied structure-guided semi-rational design to obtain a double-mutant F260W/M147Y, which showed a good isolated yield and S-stereoselectivity >99% toward 2-aminotetralin synthesis. Furthermore, the utility of this biocatalytic protocol was successfully demonstrated in the enantioselective synthesis of rotigotine via enzymatic reductive amination as the key step.

Chemoenzymatic Synthesis of Selegiline: An Imine Reductase-Catalyzed Approach.

(R)-Homobenzylic amines are key structural motifs present in (R)-selegiline, a drug indicated for the treatment of early-stage Parkinson's disease. Herein, we report a new short chemoenzymatic approach (in 2 steps) towards the synthesis of (R)-selegiline via stereoselective biocatalytic reductive amination as the key step. The imine reductase IR36-M5 mutant showed high conversion (97%) and stereoselectivity (97%) toward the phenylacetone and propargyl amine substrates, offering valuable biocatalysts for synthesizing alkylated homobenzylic amines.

Structure-guided semi-rational design of an imine reductase for enantio-complementary synthesis of pyrrolidinamine.

In this study, engineered imine reductases (IREDs) of IRED M5, originally from Actinoalloteichus hymeniacidonis, were obtained through structure-guided semi-rational design. By focusing on mutagenesis of the residues that directly interact with the ketone donor moiety, we identified two residues W234 and F260, playing essential roles in enhancing and reversing the stereoselectivity, respectively. Moreover, two completely enantio-complementary variants S241L/F260N (R-selectivity up to 99%) and I149D/W234I (S-selectivity up to 99%) were achieved. Both variants showed excellent stereoselectivity toward the tested substrates, offering valuable biocatalysts for synthesizing pyrrolidinamines. Its application was demonstrated in a short synthesis of the key intermediates of potential drug molecules leniolisib and JAK1 inhibitor 4, from cheap and commercially available pro-chiral N-Boc-piperidone 1 (2 and 3 steps, respectively).

Er Miao San, a traditional Chinese herbal formula, attenuates complete Freund's adjuvant-induced arthritis in rats by regulating Th17/Treg cells.

Context: Er Miao San (EMS) is a traditional Chinese medicine composed of Atractylodis Rhizoma and Phellodendri Cortex in a 1:1 weight ratio. EMS has been used to treat rheumatism in China for many years.Objective: To evaluate the anti-arthritic activity of EMS extract on adjuvant-induced arthritis (AA) in Sprague-Dawley rats and to clarify its mechanisms of action.Materials and methods: EMS (0.75, 1.5 and 3 g/kg, once daily) was orally administered from day 18 after immunization to day 31. The effects of EMS on AA rats were evaluated by histopathological examination, paw swelling and polyarthritis index. The proliferation of fibroblast-like synoviocyte (FLS) and T cells was detected by CCK-8. The percentages of Th17 cells and Treg cells in splenocytes were determined by flow cytometry. Levels of cytokines in serum were detected by ELISA.Results: EMS treatment significantly decreased the paw volume (from 1.20 to 0.81), polyarthritis index (from 9.56 to 4.46) and alleviated ankle joint histopathology in AA rats. EMS inhibited the proliferation of FLS and T cells. Furthermore, EMS treatment decreased Th17 cells (from 4.62 to 2.08%) and increased Treg cells (from 2.77 to 4.75%) in splenocytes. The levels of IL-17A, TNF-α and IL-6 were remarkably decreased in the serum of EMS-treated rats, whereas the levels of IL-10 and TGF-ß1 were significantly increased.Conclusions: EMS exhibits anti-arthritic activity in the AA model by regulating the balance of cytokines and the ratio of Th17 and Treg cells. These insights may provide an experimental basis for the clinical treatment of RA.

Novel 6a,12b-Dihydro-6H,7H-chromeno[3,4-c] chromen-6-ones: Synthesis, Structure and Antifungal Activity.

A new series of coumarin derivatives, 7-hydroxy-7-(trifluoromethyl)-6a,12b-dihydro-6H,7H-chromeno[3,4-c]chromen-6-ones 3a-p, were synthesized via Michael addition, transesterification and nucleophilic addition from the reaction of 3-trifluoroacetyl coumarins and phenols in the presence of an organic base. The products were characterized by infrared spectroscopy (IR), hydrogen nuclear magnetic resonance spectroscopy (1H-NMR), carbon nuclear magnetic resonance spectroscopy (13C-NMR) and high-resolution mass spectrometer (HRMS). Single crystal X-ray analysis of compounds 3a and 3n clearly confirmed their assigned chemical structures and their twisted conformations. Compound 3a crystallized in the orthorhombic system, Pbca, in which a = 8.6244(2) Å, b = 17.4245(4) Å, c = 22.5188(6) Å, α = 90°, ß = 90°, γ = 90°, v = 3384.02(14) Å3, and z = 8. In addition, the mycelial growth rate method was used to examine the in vitro antifungal activities of the title compounds 3a-p against Fusarium graminearum and Fusarium monitiforme at 500 µg/mL. The results showed that compound 3l exhibited significant anti-Fusarium monitiforme activity with inhibitory index of 84.6%.

Estimation of stature by using the dimensions of the right hand and right foot in Han Chinese adults.

The Han Chinese people are the main ethnic group in China and the largest ethnic group in the world. The dimensions of the hands and feet have been successfully used for the estimation of stature. A total of 26,927 healthy adult subjects, comprising 13,221 men and 13,706 women, were recruited. The survey samples were chosen through random cluster sampling. The mean values were significantly higher in men than those in women for all measurements (P<0.001). All the measurements showed a statistically significant correlation with stature (P<0.01). The combination of the right hand length and the right foot length was the best predictor of stature because it had the lowest standard error of estimate. The use of multiple regression equations yielded better results than did the use of linear regression equations. The accuracy of stature prediction ranged from ±4.81 to ±6.39 cm. The present study was of great importance with regards to improving the physical anthropology database of ethnic groups in China.

Physical characteristics of Chinese Hakka.

Using standard and internationally validated methods, 86 anthropologic characteristics were determined in 650 male (305 from urban areas and 345 from rural areas) and 704 female (331 from urban areas, 373 from rural areas) Chinese Hakka adults living in Guangdong and Jiangxi. The data were used to calculate 24 anthropologic indices, which were analyzed statistically. The physical characteristics of Hakka subjects were analyzed and compared with reference ethnic data. There were four main findings of this study. First, a small proportion of Hakka adults had an eye fold on the upper eyelid, but a large proportion had a mongoloid fold. The eye slits were narrow in most adults, had a medium nasal root height and straight bridges, and most of the external angles were prominent. The nasal base was upturned in most men. The distributions of the three types of nasal base in women were similar. The proportions of subjects with middle and high alae nasi heights were high and similar. Males with a maximum nostril diameter were mostly classified as transverse and oblique, while many women were classified as transverse and had relatively wide alae nasi. The round lobe type was the most common. Upper lip skin height was mostly classified as medium. Lips were classified as thin. The hair was black, eyes were brown, and the skin was yellowish. Second, the head length was long in male Hakka. The minimum frontal breadth, face breadth, lip height, and interocular breadth were similar to those of North-Asian populations. Meanwhile, head breadth, morphological facial height, nose breadth, mouth breadth, and nose height were similar to those of South-Asian populations. Head length was long in female Hakka. The minimum frontal breadth, face breadth, lip height, and interocular breadth were similar to those of North-Asian populations. Head breadth, nose breadth, and mouth breadth were similar to those of South-Asian populations. Third, the stature of male and female Hakka in urban and rural areas was classified as medium. The proportions of male and female Hakka classified as mesocephaly (length-breadth index of the head), hypsicephalic type, metriocephalic type (breadth-height index of the head) mesorrhiny, long trunk, subbrachyskelic type, broad shoulder breadth, and narrow distance between iliac crests were higher than those of other types. Finally, principal component analyses showed that the physical characteristics of Hakka were between those of South-Asian and North-Asian ethnic populations, but were generally closer to those of North-Asian populations in China.

[Age variations of head-face morphological traits of Hakka in Guangdong province].

OBJECTIVE: To investigate the age variations of head-face morphological traits of Hakka in Guangdong Province. METHODS: Thirty-eight physical indices of head and face of 671 Hakka adults (151 urban males, 181 urban females, 162 rural males and 177 rural females) from Meizhou city of Guangdong were investigated. Twelve physical indices of head and face were calculated and counted its indices distributions. The age changes of morphological traits of head and face were analyzed. RESULTS: With the age growing, the rate of eyefold of the upper eyelid was increased, and the Mongoloid fold decreased, the direction of eyeslits tended to level, nasal root height dropped, the zygomatic projection was more projected, the eye color turned to lighter, the upper red lips became thinner; medium-sized facial height, nasal height, upper lip skin height, physiognomic ear length, physiognomic ear breadth and breadth of alae nasi were decreased. The index of mouth breadth, morphological facial skin fold were positively correlated with the age. The index of minimum frontal breadth, face breadth, bigonial diameter, interocular breadth, external biocular breadth, lip height, thickness of lips and horizontal head circumference were negatively correlated with the age. With the age growing, morphological facial index and vertical cephalo-facial index was ascending. Moreover, length-height index of head, transverse frontoparietal index, zygomatico-frontal index and lip index were declining. CONCLUSION: With the age growing, the head and face measurements, physical indices and the proportion of observed indices have changed in Hakka in Guangdong province.