iScience
·
2023
·
IF 5.8
Luxian Guo,Yangming Ding,Hua Wang,Yuxuan Liu,Qian Qiang,Qi Luo,Fei Song,Changzhi Li
The catalytic conversion of lignin into N-containing chemicals is of great significance for the realization of value-added biorefinery concept. In this article, a one-pot strategy was designed for the transformation of lignin β-O-4 model compounds to imidazo[1,2-a]pyridines in yields up to 95% using 2-aminopyridine as a nitrogen source. This transformation involves highly coupled cleavage of C-O bonds, sp 3 C-H bond oxidative activation, and intramolecular dehydrative coupling reaction to construction of N-heterobicyclic ring. With this protocol, a wide range of functionalized imidazo[1,2-a]pyridines sharing the same structure skeleton as those commercial drug molecules, such as Zolimidine, Alpidem, Saripidem, etc., were synthesized from different lignin β-O-4 model compounds and one β-O-4 polymer, emphasizing the application feasibility of lignin derivatives in N-heterobicyclic pharmaceutical synthesis.
研究领域:
有机化学
·
生物炼制
·
药物化学
✓ 已验证
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Qiuli Wang,Jiahao Meng,Lingling Huang,Feng Wu,Xue Yi,Guanghao Su,Ying Li,Zhenqing Hou,Zhongxiong Fan
How to efficiently synthesize toxic chemo-drugs in the hypoxia tumor microenvironment still faces a huge challenge. Herein, we have tailored engineered vehicle-free nanoreactors by coordination-driven co-assembly of photosensitizer indocyanine green (ICG), transition metal platinum (Pt), and nontoxic 1,5-dihydroxynaphthalene (DHN) to self-amplify O2 and cascade chemo-drug synthesis in tumor cells for self-reinforcing hypoxic oncotherapy. Once vehicle-free nanoreactors are internalized into tumor cells, they show a serious instability that results in rapid disassembly and on-demand drug release under the stimuli of acidic lysosome and laser radiation. Notably, the released Pt can efficiently decompose the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia, which is conducive to enhancing the photodynamic therapy (PDT) efficiency of the released ICG. Complementarily, a large amount of the 1O2 generated by PDT can efficiently oxidize the released nontoxic DHN into the highly toxic chemo-drug juglone. Therefore, such vehicle-free nanoreactors can achieve intracellular on-demand cascade chemo-drug synthesis and self-reinforce photo-chemotherapeutic efficacy on the hypoxic tumor. On the whole, such a simple, flexible, efficient, and nontoxic therapeutic strategy will broaden the study of on-demand chemo-drug synthesis and hypoxic oncotherapy.
研究领域:
癌症治疗
·
纳米医学
·
生物化学
·
材料科学
✓ 已验证
DOI
PubMed
高影响因子
APPLIED CATALYSIS A-GENERAL
·
2025
·
IF 4.8
Fangxu Shi,Fuxin Liang,Yulin Wei,Junyan Wu,Sai Huang,Honglei Wang,Zhi Wang,Guopu Shi
The hydrogenation-catalyzed synthesis of mirabellone, a drug for the treatment of overactive bladder (OAB), faces the challenge of catalytic efficiency and selectivity regulation of its core intermediate. In this study, we propose an innovative strategy for constructing a Pd/B-Al 2 O 3 composite catalytic system on a foam ceramic substrate using the impregnation method, and systematically investigate the modulation mechanism of different boron doping ratios on the catalyst's performance. Experimental and density functional theory studies demonstrate that the incorporation of boron synergistically enhances surface adsorption of reaction intermediates, facilitates the efficient reduction of PdO, and precisely modulates the distribution of acidic sites, thereby establishing a catalytic environment more favorable for the selective reduction of nitro groups. This catalyst, characterized by its unique three-dimensional pore structure and the interface synergistic effect resulting from boron modification, enables a uniform distribution of catalytically active centers and enhances the efficiency of reaction mass transfer. Through the optimization of process parameters, the yield of the target product was significantly improved, providing an innovative technological path for the preparation of the key intermediate of mirabilon.
研究领域:
催化化学
·
材料科学
·
计算化学
·
药物合成
·
化学工程
✓ 已验证
产品关联
DOI
高影响因子
ACS Catalysis
·
2025
·
IF 13.1
Yuanzhen Zhang,Xiaozheng Wang,Xianqi Yin,Tingting Huang,Shuangjun Lin
Chiral N-heterocyclic amines containing nonadjacent stereocenters are essential and valuable synthons for the synthesis of various pharmaceuticals. ω-Transaminases (ω-TAs) are promising biocatalysts for the construction of chiral amine scaffolds. However, the remote stereocontrol in their synthesis remains challenging. Herein, we reported an enzymatic approach of kinetic resolution–asymmetric amination for synthesizing highly diastereoselective and enantioselective N-heterocyclic amines with remote stereocenters, catalyzed by only one ω-TA. An enzyme mining framework EnzSeer was developed to identify a ω-TA from Ancylobacter lacus (AlTA) that showed moderate activity and stereoselectivity toward 1-Boc-2-methyl-piperidin-5-one (1), a non-natural N-heterocyclic ketone. The structure-guided engineering of the active pocket of AlTA coupled with computational optimization of its peripheral regions significantly enhanced the catalytic performance of AlTA. The best mutant M3 exhibited a 17-fold improvement in catalytic efficiency (kcat/Km) and 118-fold increase in half-life at 45 °C. Employing the engineered enzyme, multiple chiral N-heterocyclic amines were synthesized with up to >99% ee, >95% de, and 99% conversion. The practical synthesis performance of M3 was confirmed through gram-scale synthesis of a key intermediate of ritlecitinib, achieving 38% yield, >99% ee, and 94% de. This work presents an EnzSeer framework for mining function-specific enzymes and provides engineered biocatalysts with high catalytic activity and thermostability, facilitating the development of an enzymatic pathway for producing diverse pharmaceutical chiral N-heterocyclic amines with nonadjacent stereocenters.
研究领域:
生物催化
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有机合成
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药物化学
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酶工程
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立体化学
·
药物合成
✓ 已验证
DOI
高影响因子
JOURNAL OF ORGANIC CHEMISTRY
·
2017
·
IF 4.849
Qiujie Tang,Zhaogang Bian,Wei Wu,Jin Wang,Ping Xie,Charles U. Pittman,Jr.,Aihua Zhou
The method for constructing C–S bonds is very important in organic synthesis. Here a new sulfenylation method to generate flavone thioether derivatives was developed by employing aromatic or alkyl halides, S powder and Na2S2O3 as reactants. Good yields of regioselective Calkyl–S and Caryl–S-substituted flavones were generated under relatively environmentally friendly and simple conditions. This method might be potentially applicable to large scale production, and it enriches current sulfenylation methods.
研究领域:
有机化学
·
药物合成
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ORGANIC CHEMISTRY
·
2023
·
IF 3.6
Meiqiong Zheng,Chao Huang,Jian-Zhong Yan,Shu-Li Xie,Shao-Jia Ke,Hai-Dong Xia,Ya-Nan Duan
It is highly desirable to avoid using rare or toxic metals for oxidative reactions in the synthesis of pharmaceuticals and fine chemicals. Hypervalent iodine compounds are environmentally benign alternatives, but their catalytic use has been quite limited. Herein, the protocol for in situ hypoiodite-catalyzed oxidative rearrangement of chalcones is first realized under mild and metal-free conditions, which provided a nontoxic, environmental-benign, and catalytic alternative to the thallium-based protocol. Also, the applicability and effectiveness of this catalytic protocol got well demonstrated via gram-scale synthesis and product derivatization. What is more, control and NMR tracking experiments were performed to figure out the possible catalytic species and intermediates.
研究领域:
有机化学
·
药物合成
·
环境化学
✓ 已验证
DOI
PubMed
高影响因子
ENZYME AND MICROBIAL TECHNOLOGY
·
2021
·
IF 3.493
Yingying Zhou,Yu Wang,Xi Chen,Jinhui Feng,Min Wang,Qiaqing Wu,Dunming Zhu
Enzymatic stereospecific reduction of 17-oxosteroids offers an attractive approach to access 17β-hydroxysteroids of pharmaceutical importance. In this study, by adjusting the flexibility of α6-helix at the substrate entrance of the alcohol dehydrogenase from Ralstonia sp. (RasADH), the catalytic activity toward the stereospecific 17β-reduction of androstenedione was improved without sacrifice of the enantioselectivity. Among the mutants, F205I and F205A exhibited up to 623- and 523-fold improvement in catalytic efficiency , respectively, towards a range of different 17-oxosteroids compared to the wild-type enzyme. The corresponding 17β-hydroxysteroids were prepared in optically pure form with high space-time productivity and isolated yields using F205I as the biocatalyst, indicating that these mutants are promising biocatalysts for this useful transformation. These results suggest that modulating the flexibility of the active site lid offers an effective approach to engineer alcohol dehydrogenase for accommodating bulky steroidal substrates.
研究领域:
生物化学
·
药物合成
✓ 已验证
DOI
高影响因子
Bioresources and Bioprocessing
·
2021
·Vol. 8
·期 1
·1-9
·
IF 4.578
Ni Zi-Fu,Xu Pei,Zong Min-Hua,Lou Wen-Yong
Enzymatic asymmetric amination addition is seen as a promising approach for synthesizing amine derivatives, especially unnatural amino acids, which are valuable precursors to fine chemicals and drugs. Despite the broad substrate spectrum of methylaspartate lyase (MAL), some bulky substrates, such as caffeic acid, cannot be effectively accepted. Herein, we report a group of variants structurally derived from Escherichia coli O157:H7 MAL ( Ec MAL). A combined mutagenesis strategy was used to simultaneously redesign the key residues of the entrance tunnel and binding pocket to explore the possibility of accepting bulky substrates with potential application to chiral drug synthesis. Libraries of residues capable of lining the active center of Ec MAL were then constructed and screened by an effective activity solid-phase color screening method using tyrosinase as a cascade catalyst system. Activity assays and molecular dynamics studies of the resultant variants showed that the substrate specificity of Ec MAL was modified by adjusting the polarity of the binding pocket and the degree of flexibility of the entrance tunnel. Compared to M3, the optimal variant M8 was obtained with a 15-fold increase in catalytic activity. This structure-based protein engineering of Ec MAL can be used to open new application directions or to develop practical multi-enzymatic processes for the production of various useful compounds.
研究领域:
生物化学
·
蛋白质工程
·
药物合成
✓ 已验证
DOI
PubMed
高影响因子
Antioxidants
·
2022
·Vol. 11
·期 6
·1044
·
IF 7.675
Yuanying Li,Pengpeng Zhang,Zhoutong Sun,Huanhuan Li,Ran Ge,Xiang Sheng,Wuyuan Zhang
Calcitriol is an active analog of vitamin D3 and has excellent physiological activities in regulating healthy immune function. To synthesize the calcitriol compound, the concept of total synthesis is often adopted, which typically involves multiple steps and results in an overall low yield. Herein, we envisioned an enzymatic approach for the synthesis of calcitriol. Peroxygenase fromAgrocybe aegerita(AaeUPO) was used as a catalyst to hydroxylate the C-H bond at the C-25 position of alfacalcidol and yielded the calcitriol in a single step. The enzymatic reaction yielded 80.3% product formation in excellent selectivity, with a turnover number up to 4000. In a semi-preparative scale synthesis, 72% isolated yield was obtained. It was also found thatAaeUPO is capable of hydroxylating the C-H bond at the C-1 position of vitamin D3, thereby enabling the calcitriol synthesis directly from vitamin D3.Keywords:peroxygenases;oxyfunctionalization;active vitamin D;calcitriol;biocatalysis
研究领域:
生物化学
·
药物合成
·
酶工程
✓ 已验证
DOI
PubMed
高影响因子
Catalysts
·
2023
·Vol. 14
·期 1
·23
·
IF 3.9
Zi-Han Zhang,An-Qi Wang,Bao-Di Ma,Yi Xu
The effective synthesis ofN-benzyl cyclo-tertiary amines using imine reductase, key components in natural products and pharmaceutical synthesis, is a green approach. Traditional methods faced challenges with enzyme activity and selectivity. This study focused on enhancingMesorhizobiumimine reductase (MesIRED) for betterN-benzyl cyclo-tertiary amine production. Through alanine scanning and consensus mutation, 12 single-siteMesIRED mutants were identified from 23 candidates, showing improved conversion ofN-benzylpyrrolidine andN-benzylpiperidine. Notably, mutants from I177, V212, I213, and A241 significantly boosted conversions. The best-performing mutant forN-benzylpyrrolidine,MesIREDV212A/I213V(M1), increased conversion from 23.7% to 74.3%. ForN-benzylpiperidine,MesIREDV212A/I177A/A241I(M2) enhanced conversion from 22.8% to 66.8%. Tunnel analysis revealed M1 and M2 have more efficient tunnels for larger product movement compared to wild-typeMesIRED. Using recombinantE. colicoexpressingMesIRED and glucose dehydrogenase (GDH), high conversions were achieved: 75.1% forN-benzylpyrrolidine (M1) and 88.8% forN-benzylpiperidine (M2). A preparative experiment resulted in 86.2% conversion and 60.2% yield forN-benzylpiperidine. This research offers an efficient method for engineering IRED, significantly improving conversion and selectivity forN-benzyl cyclo-tertiary amines, aiding drug synthesis and providing insights into rational design of other enzymes.Keywords:imine reductase;N-benzyl cyclo-tertiary amines;alanine scanning;consensus mutation;whole-cell biocatalysis;coexpression
研究领域:
生物化学
·
酶工程
·
药物合成
✓ 已验证
DOI
高影响因子
CRYSTENGCOMM
·
2018
·Vol. 20
·期 8
·1151-1157
·
IF 3.304
Qiangwen Fan,Xiaowei Duan,Hong Yan
The solid state [2 + 2] photocycloaddition of N,N′-diacyl-1,4-dihydropyrazines has been investigated using thiourea as a template to preorient the reactants in the crystalline state in a manner that is beneficial for the [2 + 2] photocycloaddition. The structures of the photoadducts, syn-dimers and cage-dimers, were determined using NMR and single-crystal X-ray diffraction. According to the topochemical principles used to assess the feasibility of solid state photochemical [2 + 2] cycloaddition, topological analysis of cocrystals consisting of the N,N′-diacyl-1,4-dihydropyrazines and thiourea, as well as the syn-dimers, was performed to investigate the influence of packing modes and non-covalent interactions on their solid state photoreactivity. The results showed that the solid state [2 + 2] reactivities of both the N,N′-diacyl-1,4-dihydropyrazines assembled using thiourea and the syn-dimers were controlled by the topochemical orientation of the potentially reactive double bonds and the H-bonding interactions within the adjacent reactive molecules.
研究领域:
有机化学
·
光化学
·
晶体工程
·
超分子化学
·
药物合成
✓ 已验证
DOI
高影响因子
CATALYSIS LETTERS
·
2013
·Vol. 143
·期 5
·463-468
·
IF 2.244
Zhu Anlian,Li Qianqian,Li Lingjun,Wang Jianji
Abstract A series of choline-based ionic liquids (CIL) have been synthesized in this work. The results suggested that both the cations and the anions have significant influences on their properties such as thermostabilities, acidities and their performances for the synthesis of 3,4-dihydro-2(H)-pyrimidinones. The optimized catalytic system based on the CIL [DMEA][HSO 4 ] for the Biginelli reactions benefits from the wide substrates tolerance, benign reaction conditions, easy work-up procedures, and the feasible reusability of the ionic liquid. Graphical Abstract The thermostabilities, acidities, and the catalytic activities for the Biginelli reactions are all follows the sequence of [DMEA][HSO 4 ] > [Choline] [HSO 4 ] > [DMEA][H 2 PO 4 ] > [Choline] [H 2 PO 4 ] .
研究领域:
有机化学
·
催化化学
·
药物合成
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）