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Featured researches published by Zhen Xi.


Angewandte Chemie | 2009

A Highly Sensitive Fluorescence Probe for Fast Thiol-Quantification Assay of Glutathione Reductase†

Long Yi; Heyang Li; Lu Sun; Liangliang Liu; Caihong Zhang; Zhen Xi

Fast detection of cellular thiols in aqueous medium was achieved using a newly developed fluorescence probe (see picture). Based on this probe, a high-throughput fluorescence assay for glutathione reductase was developed.


Journal of Agricultural and Food Chemistry | 2010

Design, synthesis, and 3D-QSAR analysis of novel 1,3,4-oxadiazol-2(3H)-ones as protoporphyrinogen oxidase inhibitors.

Li-Li Jiang; Ying Tan; Xiao-Lei Zhu; Zhi-Fang Wang; Yang Zuo; Qiong Chen; Zhen Xi; Guang-Fu Yang

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has been identified as one of the most significant action targets for a large chemically diverse family of herbicides that exhibit some interesting characteristics, such as low use rate, low toxicity to mammals, and low environmental impact. As a continuation of research work on the development of new PPO inhibitors, some benzothiazole analogues of oxadiargyl, an important PPO-inhibiting commercial herbicide, were designed and synthesized by ring-closing of the substituents at the C-4 and C-5 positions. The bioassay results indicated that the series 8, 9, and 10 have good PPO inhibition activity with k(i) values ranging from 0.25 to 18.63 microM. Most interestingly, 9l, ethyl 2-((5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-2(3H)-yl)-6-fluorobenzothiazol-2-yl)sulfanyl) propanoate, was identified as the most promising candidate due to its high PPO inhibition effect (k(i) = 1.42 microM) and broad spectrum postemergence herbicidal activity at the concentration of 37.5 g of ai/ha.


Journal of Chemical Information and Modeling | 2007

Rational design based on bioactive conformation analysis of pyrimidinylbenzoates as acetohydroxyacid synthase inhibitors by integrating molecular docking, CoMFA, CoMSIA, and DFT calculations.

Yan-Zhen He; Yuan-Xiang Li; Xiao-Lei Zhu; Zhen Xi; Congwei Niu; Jian Wan; Li Zhang; Guang-Fu Yang

Pyrimidinylthiobenzoates constitute an important kind of herbicides targeting acetohydroxyacid synthase (AHAS, EC 2.2.1.6), which catalyze the first common step in branched-chain amino acid biosynthesis. Due to the symmetry of 4,6-dimethoxypyrimidyl, there are two kinds of conformation of pyrimidinylthiobenzoates: ones phenyl is left-extending (named conformation-L); the others phenyl is right-extending (named conformation-R). On the basis of the assumption that 3D quantitative structure-activity relationship (QSAR) models derived from the bioactive conformation should give the best result, a strategy of density-functional-theory-based 3D-QSAR was proposed to identify the bioactive conformation of pyrimidinylthiobenzoates by integrating the techniques of molecular docking, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and density functional theory calculation. The combination of three criteria of q2, r2, and r2pred obtained from CoMFA and CoMSIA analyses clearly indicated that conformation-R rather than conformation-L might be the bioactive conformation for pyrimidinylthiobenzoates. A further comparison between the two binding modes indicated that pyrimidinylthiobenzoates and sulfonylureas have very similar binding sites, such as Trp586, Arg380, and Pro192. However, Lys251 formed H bonds with sulfonylureas rather than pyrimidinylthiobenzoates. In addition, the orientation of phenyl groups of the two classes of compounds in the binding pocket were revealed to be opposite, which explained why the mutation of Pro192 displayed different sensitivity to sulfonylureas and pyrimidinylthiobenzoates. On the basis of the understanding of interactions between pyrimidinyl-thiobenzoates and AHAS, we designed and synthesized six 8-(4,6-dimethoxypyrimidin-2-yloxy)-4-methylphthalazin-1-one derivatives according to the 3D-QSAR models. The excellent correlation between the tested Ki values against wild-type A. thaliana acetohydroxyacid synthase and the predicted IC50 values demonstrated the high reliability of the established 3D-QSAR models. To our knowledge, this is the first report highlighting the binding mode of herbicidal pyrimidinylthiobenzoates, which consisted of the reported results of herbicide resistance.


Bioorganic & Medicinal Chemistry | 2010

Design, syntheses and 3D-QSAR studies of novel N-phenyl pyrrolidin-2-ones and N-phenyl-1H-pyrrol-2-ones as protoporphyrinogen oxidase inhibitors.

Li Zhang; Yin Tan; Neng-Xue Wang; Qiong-You Wu; Zhen Xi; Guang-Fu Yang

The characteristics of low application rates, good crop selectivity, low residue and environmental safety exhibited by Protoporphyrinogen oxidase (PPO, EC 1.3.3.4)-inhibiting herbicides have attracted a world-wide research interests. As continuation of our research work on the development of new PPO inhibitors, a series of mono-carbonyl analogues of cyclic imides, N-phenyl pyrrolidin-2-ones and N-phenyl-1H-pyrrol-2-ones, were designed and synthesized based on previously established DFT-QSAR results. The PPO inhibition activities of 29 newly synthesized compounds were tested and a predictive comparative molecular field analysis (CoMFA) model was established with the conventional correlation coefficient r(2)=0.980 and the cross-validated coefficient q(2)=0.518. According to the CoMFA model, the substituent effects on the PPO inhibition activity were explained reasonably. Further greenhouse assay showed that 2-(4-chloro-2-fluoro-5-propoxy-phenyl)-2,3,4,5,6,7-hexahydro-isoindol-1-one (C(6), k(i)=0.095μM) and 2-(5-allyloxy-4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-isoindol-1-one (C(7), k(i)=0.12μM) displayed excellent post-emergency herbicidal activity at the concentration of 150g.ai/ha against seven tested weeds. Due to their high PPO inhibition effect and broad spectrum herbicidal activity, these two compounds have the potential for further study on crop selectivity and field trial. These results confirmed once again that only one of the carbonyl groups of cyclic imides is essential to the PPO inhibition activity.


Journal of Computational Chemistry | 2006

Development of a general quantum-chemical descriptor for steric effects : Density functional theory based QSAR study of herbicidal sulfonylurea analogues

Zhen Xi; Zhihong Yu; Congwei Niu; Shurong Ban; Guang-Fu Yang

Quantitative structure‐activity relationship (QSAR) analysis has become one of the most effective approaches for optimizing lead compounds and designing new drugs. Although large number of quantum‐chemical descriptors were defined and applied successfully, it is still a big challenge to develop a general quantum‐chemical descriptor describing the bulk effects more directly and effectively. In this article, we defined a general quantum‐chemical descriptor by characterizing the volume of electron cloud for specific substituent using the method of density functional theory. The application of our defined steric descriptors in the QSAR analysis of sulfonylurea analogues resulted in four QSAR models with high quality (the best model: q2 = 0.881, r2 = 0.901, n = 35, s = 0.401, F = 68.44), which indicated that this descriptor may provide an effective way for solving the problem how to directly describe steric effect in quantum chemistry‐based QSAR studies.


Bioorganic & Medicinal Chemistry | 2009

Design and synthesis of N-2,6-difluorophenyl-5-methoxyl-1,2,4-triazolo[1,5-a]-pyrimidine-2-sulfonamide as acetohydroxyacid synthase inhibitor.

Chao-Nan Chen; Lili Lv; Feng-Qin Ji; Qiong Chen; Hui Xu; Congwei Niu; Zhen Xi; Guang-Fu Yang

Triazolopyrimidine-2-sulfonamide belongs to a herbicide group called acetohydroxyacid synthase inhibitors. With the aim to discover new triazolopyrimidine sulfonanilide compounds with high herbicidal activity and faster degradation rate in soil, the methyl group of Flumetsulam (FS) was modified into a methoxy group to produce a new herbicidal compound, N-2,6-difluorophenyl-5-methoxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (experimental code: Y6610). The enzymatic kinetic results indicated that compound Y6610 and FS have k(i) values of 3.31x10(-6) M and 3.60x10(-7) M against Arabidopsis thaliana AHAS, respectively. The 10-fold lower enzyme-inhibiting activity of Y6610 was explained rationally by further computational simulations and binding free energy calculations. In addition, compound Y6610 was found to display the same level in vivo post-emergent herbicidal activity as FS against some broad-leaf weeds and good safety to rice, maize, and wheat at the dosages of 75-300 gai/ha. Further determination of the half-lives in soil revealed that the half-life in soil of Y6610 is 3.9 days shorter than that of FS. The experimental results herein showed that compound Y6610 could be regarded as a new potential acetohydroxyacid synthase-inhibiting herbicide candidate for further study.


Journal of Agricultural and Food Chemistry | 2011

Design and syntheses of novel N-(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione and N-(benzothiazol-5-yl)isoindoline-1,3-dione as potent protoporphyrinogen oxidase inhibitors.

Li-Li Jiang; Yang Zuo; Zhi-Fang Wang; Yin Tan; Qiong-You Wu; Zhen Xi; Guang-Fu Yang

Discovery of protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors has been one of the hottest research areas in the field of herbicide development for many years. As a continuation of our research work on the development of new PPO-inhibiting herbicides, a series of novel N-(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-diones (1a-p) and N-(benzothiazol-5-yl)isoindoline-1,3-diones (2a-h) were designed and synthesized according to the ring-closing strategy of two ortho-substituents. The bioassay results indicated that some newly synthesized compounds exhibited higher PPO inhibition activity than the control of sulfentrazone. Compound 1a, S-(5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl) O-methyl carbonothioate, was identified as the most potent inhibitor with k(i) value of 0.08 μM, about 9 times higher than that of sulfentrazone (k(i) = 0.72 μM). Further green house assay showed that compound 1b, methyl 2-((5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl)thio)acetate, exhibited herbicidal activity comparable to that of sulfentrazone even at a concentration of 37.5 g ai/ha. In addition, among six tested crops, wheat exhibited high tolerance to compound 1b even at a dosage of 300 g ai/ha. These results indicated that compound 1b might have the potential to be developed as a new herbicide for weed control of wheat field.


The FASEB Journal | 2010

Comprehensive analysis of sequence-specific stability of siRNA

Junmei Hong; Yuanyu Huang; Jun Li; Fan Yi; Jie Zheng; Huang Huang; Na Wei; Yongqiang Shan; Mingrui An; Hongyan Zhang; Jianguo Ji; Peizhuo Zhang; Zhen Xi; Quan Du; Zicai Liang

Double-stranded small interfering RNAs (siRNAs) are important modulators of biological processes and hold great promise for therapeutic applications. However, serum processing of synthetic siRNAs is still largely unknown. To address this issue, serum degradation assays of 125 siRNAs were first performed in this study. Four siRNA categories of distinct serum stability were identified, including a group of siRNAs that were stable in their native form for both in vitro and in vivo assays. Fine mapping of the cleavage events occurring in serum treatment demonstrated that most occurred at two vulnerable sites, leading to a speculation that rational modification of these sites might protect most siRNAs from serum degradation. For proof of concept, an exhaustive siRNA modification study was performed. In addition to the consistent stabilization pattern revealed at these sites, our study further showed that a single modification made at the cleavage site stabilized the siRNAs to a large extent, highlighting the importance of these sites in siRNA degradation. In summary, the present study provided a comprehensive picture of serum processing of siRNA as well as a starting point for a rational siRNA modification strategy, both of which are of great importance to in vivo and therapeutic applications of siRNA.


The FASEB Journal | 2011

Structural insight into human variegate porphyria disease

Xiaohong Qin; Ying Tan; Lele Wang; Zhi-Fang Wang; Baifan Wang; Xin Wen; Guang-Fu Yang; Zhen Xi; Yuequan Shen

Human protoporphyrinogen IX oxidase (hPPO), a mitochondrial inner membrane protein, converts protoporphyrinogen IX to protoporphyrin IX in the heme biosynthetic pathway. Mutations in the hPPO gene cause the inherited human disease variegate porphyria (VP). In this study, we report the crystal structure of hPPO in complex with the coenzyme flavin adenine dinucleotide (FAD) and the inhibitor acifluor‐fen at a resolution of 1.9 Å. The structural and biochemical analyses revealed the molecular details of FAD and acifluorfen binding to hPPO as well as the interactions of the substrate with hPPO. Structural analysis and gel chromatography indicated that hPPO is a monomer rather than a homodimer in vitro. The founder‐effect mutation R59W in VP patients is most likely caused by a severe electrostatic hindrance in the hydrophilic binding pocket involving the bulky, hydro‐phobic indolyl ring of the tryptophan. Forty‐seven VP‐causing mutations were purified by chromatography and kinetically characterized in vitro. The effect of each mutation was demonstrated in the high‐resolution crystal structure.—Qin, X., Tan, Y., Wang, L., Wang, Z., Wang, B., Wen, X., Yang, G., Xi, Z., Shen, Y. Structural insight into human variegate porphyria disease. FASEB J. 25, 653–664 (2011). www.fasebj.org


Journal of Structural Biology | 2010

Structural insight into unique properties of protoporphyrinogen oxidase from Bacillus subtilis

Xiaohong Qin; Lu Sun; Xin Wen; Xue Yang; Ying Tan; Hao Jin; Qiongyao Cao; Weihong Zhou; Zhen Xi; Yuequan Shen

Protoporphyrinogen IX oxidase (PPO) converts protoporphyrinogen IX to protoporphyrin IX, playing an important part in the heme/chlorophyll biosynthetic pathway. Bacillus subtilis PPO (bsPPO) is unique among PPO family members in that it is a soluble monomer, is inefficiently inhibited by the herbicide acifluorfen (AF) and has broader substrate specificity than other PPO enzymes. Here, we present the crystal structure of bsPPO bound to AF. Our structure shows that the AF molecule binds to a new site outside the previously identified inhibitor binding pocket. Most importantly, the benzene ring of the 2-nitrobenzoic acid moiety of AF lies parallel to the isoalloxazine ring of FAD at a distance of less than 3.5A, providing a framework for the interaction of FAD with the substrate protoporphyrinogen IX. Furthermore, our structure reveals that the larger substrate binding chamber and predominantly positively charged chamber surface of bsPPO are more favorable for the binding of coproporphyrinogen-III. These crystallographic findings uncover biochemically unique properties of bsPPO, providing important information for further understanding the enzymatic mechanism.

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Long Yi

Beijing University of Chemical Technology

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Guang-Fu Yang

Central China Normal University

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Changyu Zhang

Beijing University of Chemical Technology

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Ying Tan

Central China Normal University

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Zhi-Fang Wang

Central China Normal University

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