CRYSTAL GROWTH & DESIGN
·
2024
·
IF 3.2
Yujiang Xie,Shubo Liu,Jie Sun,Weiwei Tang,Junbo Gong
Processes that allow access to enantiomerically pure drugs are of the utmost importance to maximize pharmacological activity while minimizing the side effects. This work develops a novel diastereomeric cocrystallization-induced spontaneous deracemization process for a racemic compound, dihydromyricetin (DMY), which contains two stereocenters. A pair of diastereomeric cocrystals, (2R,3R-DMY)2:R-N-benzyl-1-phenylethylamine and (2R,3R-DMY)2:S-N-benzyl-1-phenylethylamine, the latter of which is equivalent to (2S,3S-DMY)2:R-N-benzyl-1-phenylethylamine, was discovered via a complete screening of 12 chiral coformers using both slurry and liquid-assisted grinding methods. Crystal structure of these cocrystals was determined using single-crystal X-ray diffraction and reported for the first time. Enantioseparation of rac-DMY by virtue of diastereomeric cocrystals was designed and optimized through slurry and cooling crystallization methods, resulting in a product of 81% enantiomeric purity with a yield of only 31%. Further, the racemization process of DMY enantiomers with various influence factors was examined, and the optimal racemization condition that achieves simultaneous racemization of the two stereocenters was determined. Finally, a stepwise cocrystallization-induced deracemization process of rac-DMY that combines chiral resolution by cocrystallization and racemization of recycling mother liquor was developed, producing an enantiomeric purity of 97.5% and a maximal yield of 68%.
研究领域:
药学
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有机化学
·
药物化学
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产品关联
DOI
高影响因子
SAUDI PHARMACEUTICAL JOURNAL
·
2023
·
IF 4.1
Qiang Zheng,Shuai He,Song-Lin Xu,Meng-Die Ma,Min Fan,Jin-Fang Ge
Purpose To investigate the pharmacokinetics and tissue distribution of VGB racemate and its single enantiomers, and explore the potential of clinic development for single enantiomer S-VGB. Methods In the pharmacokinetics study, male Sprague-Dawley rats were gavaged with VGB racemate or its single enantiomers dosing 50, 100 or 200 mg/kg, and the blood samples were collected during 12 h at regular intervals. In the experiment of tissue distribution, VGB and its single enantiomers were administered intravenously dosing 200 mg/kg, and the tissues including heart, liver, spleen, lung and kidney, eyes, hippocampus, and prefrontal cortex were separated at different times. The concentrations of R-VGB and S-VGB in the plasma and tissues were measured using HPLC. Results Both S-VGB and R-VGB could be detected in the plasma of rats administered with VGB racemate, reaching Cmax at approximately 0.5 h with t 1/2 2–3 h. There was no significant pharmacokinetic difference between the two enantiomers when VGB racemate was given 200 mg/kg and 100 mg/kg. However, when given at the dose of 50 mg/kg, S-VGB presented a shorter t 1/2 and a higher Cl/F than R-VGB, indicating a faster metabolism of S-VGB. Furthermore, when single enantiomer was administered respectively, S-VGB presented a slower metabolism than R-VGB, as indicated by a longer t 1/2 and MRT but a lower Cmax. Moreover, compared with the VGB racemate, the single enantiomers S-VGB and R-VGB had shorter t 1/2 and MRT, higher Cmax and AUC/D, and lower Vz/F and Cl/F, indicating the stronger oral absorption and faster metabolism of single enantiomer. In addition, regardless of VGB racemate administration or single enantiomer administration, S-VGB and R-VGB had similar characteristics in tissue distribution, and the content of S-VGB in hippocampus, prefrontal cortex and liver was much higher than that of R-VGB. Conclusions Although there is no transformation between S-VGB and R-VGB in vivo, those two enantiomers display certain disparities in the pharmacokinetics and tissue distribution, and interact with each other. These findings might be a possible interpretation for the pharmacological and toxic effects of VGB and a potential direction for the development and optimization of the single enantiomer S-VGB.
研究领域:
药理学
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毒理学
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神经科学
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产品关联
DOI
PubMed
高影响因子
DYES AND PIGMENTS
·
2023
·
IF 4.5
Shibing Chen,Minqian Zhu,Xiangfei Xu,Hongyu Guo,Fafu Yang
The macrocycles with the features of large cavity, optical property and CPL response to guest simultaneously are rarely reported but very attractive based on their potential application. Herein, a macrocycle ( BiCDB-MC ) with dynamically racemic feature, inwardly directed functional groups, a large hollow with size of 1.3 nm and fluorescent property was designed and synthesized. BiCDB-MC was found to have two equally chiral conformations and was dynamically racemic in solution based on their rapidly interconvertion via macrocycle flipping. It was interesting that BiCDB-MC exhibited a selective turn-on CPL response with g lum = 0.00248 toward ursolic acid since one of the stable chiral conformations could form a more stable inclusion complex. This kind of turn-on CPL emission for dynamical-racemic macrocycle with CPL recognition for complicated natural chiral compound was described for the first time.
研究领域:
有机化学
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超分子化学
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材料科学
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DOI
高影响因子
JOURNAL OF BIOTECHNOLOGY
·
2023
·
IF 4.1
Fang-Ying Zhu,Qing Yang,Min Cao,Ken Zheng,Xiao-Jian Zhang,Qi Shen,Xue Cai,Zhi-Qiang Liu,Yu-Guo Zheng
d -(−)-Pantolactone (DPL) is a key intermediate for the production of d -(+)-pantothenate (vitamin B5). Deracemization of d , l -pantolactone (D, L -PL) through oxidizing l -(+)-pantolactone (LPL) to ketopantoyl lactone (KPL) and subsequently reducing KPL to DPL is a promising route for synthesizing DPL. Herein, a newly mined l -pantolactone dehydrogenase from Rhodococcus hoagie ( Rho LPLDH) was used for the oxidative dehydrogenation of LPL. To alleviate inclusion bodies formed by membrane-bound Rho LPLDH intracellular expression in E. coli , strategies involving chaperone assistance and decreasing induction temperature were used to achieve Rho LPLDH soluble expression. To enhance its activity, directed evolution and hydrophilicity-based engineering yielded increased catalytic activity and thermostability . 1 M LPL was efficiently converted to KPL by engineering strain CM5 co-expressing Rho LPLDH L254I/V241I/I156L/F224Q/N164K and chaperone. A “two stages in one-pot” method was employed in deracemization of 1 M D, L -PL with 91.2% yield. These results demonstrated that CM5 catalyst exhibits great potential in enzyme cascade deracemization for the production of DPL.
研究领域:
生物技术
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生物化学
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酶工程
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微生物生物技术
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产品关联
DOI
PubMed
高影响因子
BIOPROCESS AND BIOSYSTEMS ENGINEERING
·
2025
·
IF 3.6
Jin Li-Qun,Liu Meng-Dan,Guan Zi-Yu,Li Yi-Xin,Xue Ya-Ping,Liu Zhi-Qiang,Zheng Yu-Guo
DAAO is applied as a potential catalyst in the biosynthesis of L-PPT. However, its low solubility expression constrains its broader industrial application. Herein, a novel DAAO derived from Cladophialophora carrionii ( Cc DAAO) was identified, which demonstrated superior catalytic performance toward D-Ala (specific activity: 106.38 ± 1.21 U/mg, K m : 1.56 ± 0.06 mM), along with remarkable thermostability and broad substrate spectrum. Under optimal culture conditions, the soluble expression level of Cc DAAO was enhanced through a co-expression strategy with molecular chaperones, and the enzyme activity increased by 36.3% compared with the initial level. Subsequently, Cc DAAO was constructed as a fusion protein (CGD) with catalase from Geobacillus sp. CHB1 ( Gb CAT) and applied in a D-amino acid aminotransferase (DAAT)-mediated cascade system. In a 2 L reaction system, this cascade system achieved complete conversion (> 99%) of 1 M D,L-PPT within 8 h, exhibiting a yield of 11.26 g/L/h for PPO, which represents a significant improvement over existing reports. This study presents a promising practical approach for the industrial production of optically pure L-PPT.
研究领域:
生物催化
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酶工程
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药物合成
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工业微生物
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蛋白质工程
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产品关联
DOI
PubMed
高影响因子
CHINESE JOURNAL OF CHEMISTRY
·
2021
·Vol. 39
·期 9
·2403-2409
·
IF 6
Xiao Jiang,Na Zhao,Zhibo Li
Main observation and conclusion Substantial progresses have been made toward the development of metal-free catalysts for stereoselective ring-opening polymerization (ROP) of rac -lactide. Yet the discovery of organic catalysts effective at ambient temperature remains a major challenge. Here, the bifunctional H-bonding catalyst SQ-1 containing a basic tertiary amine and squaramide motif proved to be good candidate for the stereoselective ROP of rac -lactide at room temperature, yielding stereoregular polylactide with controlled molecular weights (up to 21.1 kg/mol) and high tacticity ( P i ESC up to 0.88). Furthermore, binary H-bonding catalytic system consisting of squaramides (SQ-2 to SQ-6) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) could efficiently promote the ROP of rac -lactide at room temperature within short reaction time. Among them, the most bulky squaramide SQ-2 exhibited the best steroselectivity towards the ROP of rac -lactide without transesterification side reactions during the polymerization process. The resulting polylactides were proved to have controlled molecular weights as high as 22.2 kg/mol and narrow distributions (1.10—1.24).
研究领域:
高分子化学
·
有机化学
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产品关联
DOI
高影响因子
CRYSTAL GROWTH & DESIGN
·
2023
·
IF 3.8
Li Wang,Na Wang,Jingchen Sui,Shiyu Sun,Ziwei Feng,Guangyan Li,Hongxun Hao,Lina Zhou
The formation of a conglomerate is always attractive, which is a prerequisite for chiral resolution by a flexible and productive preferential crystallization. This present study is aimed at exploring the possibility of chiral resolution in a two racemic compound system. The racemic conglomerate of S–S and R–R was prepared by slurring RS-naproxen (RS-NAP) with RS-1-(2-naphthyl) ethylamine (RS-NEA), which was determined by powder X-ray diffraction, differential scanning calorimetry, single-crystal X-ray diffraction, and ternary solubility phase diagram. Moreover, comparative analysis of the molecular structure, stacking patterns, thermodynamic properties, and intermolecular interactions of S–S and R–S indicates that the S–S crystal is more stable. Finally, the feasibility of chiral resolution in isopropanol was explored through a seeded isothermal preferential crystallization mode, and alternative crystallization of S–S and R–R was achieved with recycling the mother liquors.
研究领域:
化学
·
药学
✓ 已验证
DOI
高影响因子
FORENSIC SCIENCE INTERNATIONAL
·
2016
·
IF 1.95
Shisheng Chen,Yanyi Lv,Dian Wang,Xiaojun Yu
Aspartic acid racemization in teeth has been increasingly used to estimate chronological age with a considerably high accuracy in forensic practice. The Chaoshan population in South China is relatively isolated in geography, and has specific lifestyle and dietary inhibits. It is still unknown whether this method is suitable for this population. The aim of this study was to analyze the relationship between chronological age and the d / l aspartic acid ratio in dentin in the third molar tooth of the Chaoshan population. Fifty-eight non-carious third molar teeth (31 mandibles and 27 maxillae), from 58 living individuals of known age (24 males and 34 females), were retrieved. Dentin was extracted from these teeth. The d - and l -aspartic acids in dentins were separated and detected by high performance liquid chromatography (HPLC). Linear regression was performed between the d / l aspartic acid ratio of dentins and chronological age. Results showed that the correlation coefficient (r) was 0.969, and the mean absolute error (MAE) was 2.19 years, its standard deviation (SD) was ±1.53 years, indicating excellent correlation. There was no significant difference in racemization rates of dentin between sexes ( P = 0.113, F = 2.6), or between mandibles and maxillae ( P = 0.964, F = 0.000). Results indicate that the ratio of the d and l forms of aspartic acid of dentins, in the third molar, is closely correlated with chronological age, special lifestyle do no obviously affect the accuracy of the age estimations by aspartic acid racemization of the dentin in the third molar and that aspartic acid racemization in the third molar dentin can be used as an accurate method to estimate chronological age in the Chaoshan population in South China.
研究领域:
法医学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED POLYMER SCIENCE
·
2023
·Vol. 140
·期 17
·e53762
·
IF 3
Guiying Tian,Huiqing Wang,Yuanyuan Song,Jun Xiang,Yiran Ying,Xurui Han,Songbo Wang,Lei Zhang,Jianping Zhang,Na Tang
Lactide is the crucial intermediate for polylactic acid (PLA) synthesis via ring-open polymerization, but it suffers low yield and low purity induced by racemization reaction. In this work, we have developed a zinc oxide-creatinine (ZnO-CR) hybrid catalyst, which offers high yield (the distilled lactide yield and pure l -lactide yield are 95.73% and 61.64%) and high purity (81.53%) for green l -lactide synthesis at the cyclization temperature of 240°C. Furthermore, NMR and HPLC results show that CR addition significantly restrains the racemization by reducing α-proton abstraction, where guanidine derived from the CR plays a main catalytic role to provide a tight association with the carbonyl oxygen in the carboxyl of L n A oligomers. Therefore, carbonyl-carbon with the enhanced electrophilicity is easier being attacked by a hydroxyl terminal of L n A oligomers, leading to high yield and high purity for lactide synthesis.
研究领域:
化学工程
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材料科学
·
催化化学
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产品关联
DOI
高影响因子
ORGANOMETALLICS
·
2022
·
IF 3.837
Hui Liu,Fen You,Xiang Hu,Yanchen Huo,Xiaochao Shi
A family of rare-earth metal complexes bearing unsymmetrical diarylamido-[PNNox] pincer ligands with diverse chiral substituents were synthesized by utilizing direct alkane elimination. NMR and X-ray diffraction analyses revealed that the scandium and lutetium complexes were mononuclear, while the yttrium complexes were binuclear via the alkoxo bridges. All rare-earth metal complexes showed high catalytic activity for ring-opening polymerization (ROP) of rac-lactide, affording heteroselective polylactide (Pr up to 0.78). The yttrium complexes exhibited higher catalytic activity and higher heteroselectivity than the scandium and lutetium complexes. Especially, slight influence of the chiral substituents on the activity and heteroselectivity was observed in the catalytic systems. The kinetic study revealed that PMe–Y catalyzed the ROP of rac-lactide in a controlled manner and the polymerization proceeded with first-order dependence on both monomer and initiator concentrations.
研究领域:
化学
·
高分子科学
·
催化反应
✓ 已验证
DOI
高影响因子
ADVANCED SYNTHESIS & CATALYSIS
·
2019
·Vol. 361
·期 13
·3191-3199
·
IF 5.451
Shuyun Ju,Mingxin Qian,Gang Xu,Lirong Yang,Jianping Wu
Optically pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids constitute an important class of building blocks for the synthesis of natural products and synthetic pharmaceuticals. However, redox deracemization of racemic 1,2,3,4-tetrahydroisoquinoline carboxylic acids as an attractive method is still challenging for the lack of suitable oxidoreductases. Herein, a D-amino acid oxidase from Fusarium solani M-0718 ( Fs DAAO) with broad substrate scope and excellent enantioselectivity was exploited through genome mining, and applied for the kinetic resolution of a number of racemic 1- and 3-carboxyl substituted tetrahydroisoquinolines to yield the corresponding ( S )-enantiomers with excellent enantiomeric excess ( ee ) values (up to >99%). By using Fs DAAO in combination with ammonia-borane in one pot, deracemization of these racemic carboxyl-substituted tetrahydroisoquinolines was achieved with conversions up to >98% and >99% ee . Preparative-scale deracemization of racemic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was also demonstrated with good isolated yields (82% and 73%, respectively) and ee >99%. Our study provides an effective method for the synthesis of enantiomeric pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids. This method is expected to provide access to chiral carboxyl-substituted 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro-ß-carbolines.
研究领域:
生物化学
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有机合成
·
酶工程
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 13
·10744
·
IF 5.6
Mingyue Hao,Minghui Wang,Danyu Zhao,Yong Shi,Ye Yuan,Junmei Li,Yunyi Zhai,Xiaofang Liu,Dong Zhou,Huatao Chen,Pengfei Lin,Keqiong Tang,Wei Liu,Yaping Jin,Aihua Wang
Brucella suis, the causative agent of brucellosis, poses a significant public health and animal husbandry threat. However, the role of the alanine racemase (alr) gene, which encodes alanine racemase inBrucella, remains unclear. Here, we analyzed analrdeletion mutant and a complemented strain ofBrucella suisS2. The knockout strain displayed an unaltered, smooth phenotype in acriflavine agglutination tests but lacked the core polysaccharide portion of lipopolysaccharide (LPS). Genes involved in the LPS synthesis were significantly upregulated in the deletion mutant. Thealrdeletion strain exhibited reduced intracellular viability in the macrophages, increased macrophage-mediated killing, and upregulation of the apoptosis markers. Bcl2, an anti-apoptotic protein, was downregulated, while the pro-apoptotic proteins, Bax, Caspase-9, and Caspase-3, were upregulated in the macrophages infected with the deletion strain. The infected macrophages showed increased mitochondrial membrane permeability, Cytochrome C release, and reactive oxygen species, activating the mitochondrial apoptosis pathway. These findings revealed that alanine racemase was dispensable inB. suisS2 but influenced the strain’s rough features and triggered the mitochondrial apoptosis pathway during macrophage invasion. The deletion of thealrgene reduced the intracellular survival and virulence. This study enhances our understanding of the molecular mechanism underlyingBrucella’s survival and virulence and, specifically, howalrgene affects host immune evasion by regulating bacterial LPS biosynthesis.Keywords:Brucella suisS2;alanine racemase;alr;lipopolysaccharide;apoptosis;mitochondrial membrane potential;intracellular survival
研究领域:
微生物学
·
分子生物学
·
传染病学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）