- Design, synthesis and biological evaluations of diverse Michael acceptor-based phenazine hybrid molecules as TrxR1 inhibitors
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A series of novel phenazine derivatives (1~27) containing the Michael acceptor scaffolds were designed and synthesized in this study. Some compounds exhibited selective cytotoxicity against Bel-7402 cancer cell line in vitro, in which compound 26 were found to have the best antiproliferative activity. Meanwhile, compound 26 showed no obvious cell toxicity against human normal liver epithelial L02 cells, which means this compound possessed a better safety potential. In the following research, compound 26 was verified to inhibit TrxR1 enzyme activity, ultimately resulting in cellular molecular mechanism events of apoptosis including growth of intracellular ROS level, depletion of reduced Trx1, liberation of ASK1 and up-regulation of p38, respectively. Together, all these evidences implicated that compound 26 acted as the TrxR1 inhibitor against Bel-7402 cells, and could activate apoptosis through the ROS-Trx-ASK1-p38 pathway.
- Zhong, Yucheng,Liu, Jing,Cheng, Xiangyu,Zhang, Hao,Zhang, Chunhua,Xia, Zhuolu,Wu, Zhongxi,Zhang, Lu,Zheng, Yuting,Gao, Zhanyu,Jiang, Zhidong,Wang, Zhixiang,Huang, Dechun,Lu, Yuanyuan,Jiang, Feng
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- Synthesis, crystal structure and bioactivity of phenazine-1-carboxylic acylhydrazone derivatives
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A phenazine-1-carboxylic acid intermediate was synthesized from the reaction of aniline and 2-bromo-3-nitro-benzoic acid. It was then esterified and reacted with hydrazine hydrate to af-ford phenazine-1-carboxylic hydrazine. Finally, 10 new hydrazone compounds 3a–3j were obtained by the condensation reaction of phenazine-1-carboxylic acid hydrazide and the respective aldehyde-containing compound. The structures were characterized by1H and13C NMR spectros-copy, MS and single crystal X-ray diffraction. The antitumor activity of the target compounds in vitro (HeLa and A549) was determined by thiazolyl blue tetrazolium bromide. The results showed that compound (E)-N′-(2-hydroxy-4-(2-(piperidine-1-yl) ethoxy) benzyl) phenazine-1-carbonyl hydrazide 3d exhibited good cytotoxic activity.
- Huang, Yali,Liang, Xi,Liu, Hua,Luo, Fang,Redshaw, Carl,Shen, Lingyi,Wu, Ning,Wu, Shouting,Xu, Hong,Yang, Xianjiong,Zhang, Qilong
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- Dual phenazine gene clusters enable diversification during biosynthesis
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Biosynthetic gene clusters (BGCs) bridging genotype and phenotype continuously evolve through gene mutations and recombinations to generate chemical diversity. Phenazine BGCs are widespread in bacteria, and the biosynthetic mechanisms of the formation of the phenazine structural core have been illuminated in the last decade. However, little is known about the complex phenazine core-modification machinery. Here, we report the diversity-oriented modifications of the phenazine core through two distinct BGCs in the entomopathogenic bacterium Xenorhabdus szentirmaii, which lives in symbiosis with nematodes. A previously unidentified aldehyde intermediate, which can be modified by multiple enzymatic and non-enzymatic reactions, is a common intermediate bridging the pathways encoded by these BGCs. Evaluation of the antibiotic activity of the resulting phenazine derivatives suggests a highly effective strategy to convert Gram-positive specific phenazines into broad-spectrum antibiotics, which might help the bacteria–nematode complex to maintain its special environmental niche.
- Shi, Yi-Ming,Brachmann, Alexander O.,Westphalen, Margaretha A.,Neubacher, Nick,Tobias, Nicholas J.,Bode, Helge B.
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p. 331 - 339
(2019/04/17)
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- Phenazine derivative serving as TrxR1 inhibitor, intermediate product, preparation methods of phenazine derivative and intermediate product and application of phenazine derivative
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The invention discloses a phenazine derivative which has a structure shown in a general formula I and serves as a TrxR1 inhibitor, an intermediate product, and a preparation method and application ofthe phenazine derivative. In the formula I, R is H or CH3; R is selected from H, CH2N(CH3)2, phenyl, (4-fluoro)-phenyl, (3-trifluoromethyl)-phenyl, (4-chloro)-phenyl and (2,5-dichloro)-phenyl; and R is H. The phenazine derivative disclosed by the invention has significant inhibitory activity on TrxR1, especially has significant anti-proliferative activity on HepG2 cell strains, and can beused for preparing anti-tumor drugs.
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- Phenazine compound containing oxazole ring and application of phenazine compound as agricultural fungicide (by machine translation)
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The present invention relates to an oxazole ring-containing phenazine compound, the use of, and such a compound as an. agricultural fungicide, wherein the compound has: the following general formula (I). A compound represented R by the, formula, #, #, STR7, #, #, wherein, R represents a, 1 - 6 hydrogen, and atom, 2-4 a R halogeno-methyl group, an amino group, a phenyl group, a methoxy group, and a phenyl group. (by machine translation)
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- Phenazine - 1 - carboxamide compounds 15 - 1 in inhibiting the application of bacteria in the strawberry gray (by machine translation)
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The invention belongs to the field of agricultural chemicals to create, in particular to phenazine - 1 - carboxamide compounds 15 - 1 in inhibiting the application of bacteria in the strawberry gray, the phenazine - 1 - carboxamide compounds 15 - 1 is to phenazine - 1 - carboxamide as a matrix, obtained by the structure. This invention adopts the exaction determine the compounds 15 - 1 to change the strawberry gray inhibition of bacteria, result display: compounds 15 - 1 with its parent are on strawberry gray can be pathogens producing inhibit function, and the suppression effect is stronger than the parent phenazine - 1 - carboxamide, nonwovens that change 15 - 1 can be used as new pesticide of strawberry gray mold prevention and control lead compound. (by machine translation)
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Paragraph 0015; 0016
(2017/08/31)
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- Application of phenazine-1-formamide modified compound 15-1 in inhibiting Sclerotinia sclerotiorum
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The invention discloses application of a phenazine-1-formamide modified compound 15-1 in inhibiting Sclerotinia sclerotiorum. The phenazine-1-formamide modified compound 15-1 is obtained with phenazine-1-formamide as a mother substance by structural modification. According to the invention, a growth rate method is adopted to measure the inhibiting effect of the phenazine-1-formamide modified compound 15-1 on Sclerotinia sclerotiorum. The results indicate that the modified compound 15-1 has good inhibitory effect on Sclerotinia sclerotiorum, and the inhibitory effect is better than that of the mother substance phenazine-1-formamide, which indicates that the modified compound 15-1 can be used as a lead compound of new pesticides for controlling Sclerotinia rot of rape.
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Paragraph 0016; 0019
(2017/08/31)
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- Phenazine carboxylate compound and use thereof
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The invention discloses a phenazine carboxylate compound which is represented by a formula I shown in the description, wherein R is selected from C4-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, aryl C1-C3 alkyl or C3-C8 cycloalkyl; the aryl is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a furan ring, a thiophene ring, a pyrazol ring, an imidazole ring and a triazole ring which are substituted by 1-5 same or different R1; R1 is selected from hydrogen, halogen, hydroxyl, amino, nitryl, cyano, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkyl amino, C1-C6 halogenated alkyl amino, C1-C6 alkoxyl or C1-C6 halogenated alkoxyl. The compound represented by the formula I has excellent sterilizing bacterial and can be used for preventing plant fungi diseases.
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- An improved synthetic method of phenazine-1-carboxylic acid
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An improved synthetic method of a natural fungicide, phenazine-1-carboxylic acid, was reported. In brief, the process constitutes of (a) one-pot synthesis of 1-methyphenazine (IV) from pyrocatechol and 3-methyl-2-aminoaniline, (b) Wohl-Ziegler bromination of IV, (c) hydrolyzation of 1-bromomethylphenazine (III) in aqueous solution of Na2CO3/N,N-dimethylformamide (1.1:1, v/v), (d) oxidation of 1-phenazinemethanol (II) by O2 under the catalyzation of N-bromosuccinimide. This method provided an effective synthesis of phenazine-1-carboxylic acid in the overall yield of 66 %.
- Zhan,Zhu,Huang,Liu,Zhu
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p. 3355 - 3360
(2015/12/05)
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- PHENAZINE DERIVATIVES AS ANTIMICROBIAL AGENTS
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The present invention provides novel phenazine derivatives, such as compounds of Formula (I) and (II), and pharmaceutically acceptable salts thereof. The compounds of the invention are expected to be anitmicrobial agents and may act by a microbial warfare strategy (e.g., a reactive oxygen species (ROS)-based competition strategy). The present invention also provides pharmaceutical compositions, kits, uses, and methods that involve the compounds of the invention and may be useful in preventing or treating a microbial infection (e.g., a bacterial infection) in a subject, inhibiting the growth and/or reproduction of a microorganism (e.g., a bacterium), killing a microorganism (e.g., a bacterium), inhibiting the formation and/or growth of a biofilm, or reducing or clearing a biofilm.
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- Phenazine antibiotic inspired discovery of potent bromophenazine antibacterial agents against Staphylococcus aureus and Staphylococcus epidermidis
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Nearly all clinically used antibiotics have been (1) discovered from microorganisms (2) using phenotype screens to identify inhibitors of bacterial growth. The effectiveness of these antibiotics is attributed to their endogenous roles as bacterial warfare agents against competing microorganisms. Unfortunately, every class of clinically used antibiotic has been met with drug resistant bacteria. In fact, the emergence of resistant bacterial infections coupled to the dismal pipeline of new antibacterial agents has resulted in a global health care crisis. There is an urgent need for innovative antibacterial strategies and treatment options to effectively combat drug resistant bacterial pathogens. Here, we describe the implementation of a Pseudomonas competition strategy, using redox-active phenazines, to identify novel antibacterial leads against Staphylococcus aureus and Staphylococcus epidermidis. In this report, we describe the chemical synthesis and evaluation of a diverse 27-membered phenazine library. Using this microbial warfare inspired approach, we have identified several bromophenazines with potent antibacterial activities against S. aureus and S. epidermidis. The most potent bromophenazine analogue from this focused library demonstrated a minimum inhibitory concentration (MIC) of 0.78-1.56 μM, or 0.31-0.62 μg mL-1, against S. aureus and S. epidermidis and proved to be 32- to 64-fold more potent than the phenazine antibiotic pyocyanin in head-to-head MIC experiments. In addition to the discovery of potent antibacterial agents against S. aureus and S. epidermidis, we also report a detailed structure-activity relationship for this class of bromophenazine small molecules.
- Borrero, Nicholas V.,Bai, Fang,Perez, Cristian,Duong, Benjamin Q.,Rocca, James R.,Jin, Shouguang,Huigens Iii, Robert W.
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p. 881 - 886
(2014/02/14)
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- Bis(phenazine-1-carboxamides): Structure-activity relationships for a new class of dual topoisomerase I/II directed anticancer drugs
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Ring-substituted bis(phenazine-1-carboxamides), linked by a - (CH2)3NMe(CH2)3- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, including P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase (topo) II targeted agents because of lower levels of the enzyme. Analogues with small, lipophilic substituents (e.g., Me, Cl) at the 9-position were the most potent inhibitors, superior to the corresponding dimeric bis(acridine-4-carboxamides) (bis-DACA analogues). Several of the compounds were preferentially (up to 2-fold) more cytotoxic toward the mutant Jurkat lines than the wild-type. To test whether this selectivity was related to topoisomerase action, the most potent of the compounds (9-methyl) was evaluated in a cell-free system. It poisoned topo I at drug concentrations of 0.25 and 0.5 μM and inhibited the catalytic activity of both topo I and topo II at concentrations of 1 and 5 μM, respectively. Results from the NCI human tumor cell line panel showed the compounds had preferential activity toward colon tumor lines (on average 9.5-fold more active in the HT29 line than in the cell line panel as a whole). Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo. In particular the 9-methyl compound was substantially more potent in this tumor model than the clinical dual topo I/II poison DACA (total dose 90 versus 400 mg/kg) with comparable activity. The bis(phenazine-1-carboxamides) are a new and interesting class of dual topo I/II-directed anticancer drugs.
- Spicer, Julie A.,Gamage, Swarna A.,Rewcastle, Gordon W.,Finlay, Graeme J.,Bridewell, David J. A.,Baguley, Bruce C.,Denny, William A.
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p. 1350 - 1358
(2007/10/03)
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- Derivatives of 1-phenazincarboxylic acid
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The important biological properties of some compounds having phenazinic rings decided upon the synthesis of new substances by condensing 1-phenazincarboxylic acid hydrazide with aromatic aldehydes. The new compounds have been characterized by IR , NMR spectra.
- Nicolae, Anca,Drǎghici, Constantin,Maior, Ovidiu,Ianculescu, Gabriela
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p. 131 - 136
(2007/10/03)
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- UNEQUIVOCAL SYNTHESIS OF PHENAZINE-1-CARBOXYLIC ACIDS: SELECTIVE DISPLACEMENT OF FLUORINE DURING ALKALINE BOROHYDRIDE REDUCTION OF N-(2-FLUOROPHENYL)-3-NITROANTHRANILIC ACIDS
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Reductive cyclization of substituted N-(2-fluorophenyl)-3-nitroanthranilic acids provides an unequivocal synthetic route to 6-, 8- and 9-substituted phenazine-1-carboxylic acids.
- Rewcastle, Gordon W,Denny, William A
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p. 1171 - 1180
(2007/10/02)
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