- Fast and Cysteine-Specific Modification of Peptides, Proteins and Bacteriophage Using Chlorooximes
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This work reports a novel chlorooxime mediated modification of native peptides and proteins under physiologic conditions. This method features fast reaction kinetics (apparent k2=306±4 M?1s?1 for GSH) and exquisite selectivity for cysteine residues. This cysteine conjugation reaction can be carried out with just single-digit micromolar concentrations of the labeling reagent. The conjugates show high stability towards acid, base, and external thiol nucleophiles. A nitrile oxide species generated in situ is likely involved as the key intermediate. Furthermore, a bis-chlorooxime reagent is synthesized to enable facile Cys-Cys stapling in native peptides and proteins. This highly efficient cysteine conjugation and stapling was further implemented on bacteriophage to construct chemically modified phage libraries.
- Chen, Fa-Jie,Zheng, Mengmeng,Nobile, Vincent,Gao, Jianmin
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supporting information
(2022/03/15)
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- Cysteine-Activated Small-Molecule H2Se Donors Inspired by Synthetic H2S Donors
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The importance of selenium (Se) in biology and health has become increasingly clear. Hydrogen selenide (H2Se), the biologically available and active form of Se, is suggested to be an emerging nitric oxide (NO)-like signaling molecule. Nevertheless, the research on H2Se chemical biology has technique difficulties due to the lack of well-characterized and controllable H2Se donors under physiological conditions, as well as a robust assay for direct H2Se quantification. Motivated by these needs, here, we demonstrate that selenocyclopropenones and selenoamides are tunable donor motifs that release H2Se upon reaction with cysteine (Cys) at pH 7.4 and that structural modifications enable the rate of Cys-mediated H2Se release to be tuned. We monitored the reaction pathways for the H2Se release and confirmed H2Se generation qualitatively using different methods. We further developed a quantitative assay for direct H2Se trapping and quantitation in an aqueous solution, which should also be operative for investigating future H2Se donor motifs. In addition, we demonstrate that arylselenoamide has the capability of Cys-mediated H2Se release in cellular environments. Importantly, mechanistic investigations and density functional theory (DFT) calculations illustrate the plausible pathways of Cys-activated H2Se release from arylselenoamides in detail, which may help understand the mechanistic issues of the H2S release from pharmacologically important arylthioamides. We anticipate that the well-defined chemistries of Cys-activated H2Se donor motifs will be useful for studying Se biology and for development of new H2Se donors and bioconjugate techniques.
- Cai, Xuekang,Cheng, Longhuai,Dong, Yalun,Huang, Haojie,Jiang, Chenyang,Kang, Xueying,Sang, Yueqian,Sun, Lu,Wen, Xin,Xi, Zhen,Yi, Long
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p. 3957 - 3967
(2022/03/08)
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- Metabolite profiling reveals a role for intercellular dihydrocamalexic acid in the response of mature Arabidopsis thaliana to Pseudomonas syringae
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The leaf intercellular space is a site of plant-microbe interactions where pathogenic bacteria such as Pseudomonas syringae grow. In Arabidopsis thaliana, the biosynthesis of tryptophan-derived indolic metabolites is induced by P. syringae infection. Using high-resolution mass spectrometry-based profiling and biosynthetic mutants, we investigated the role of indolic compounds and other small molecules in the response of mature Arabidopsis to P. syringae. We observed dihydrocamalexic acid (DHCA), the precursor to the defense-related compound camalexin, accumulating in intercellular washing fluids (IWFs) without further conversion to camalexin. The indolic biosynthesis mutant cyp71a12/cyp71a13 was more susceptible to P. syringae compared to mature wild-type plants displaying age-related resistance (ARR). DHCA and structural analogs inhibit P. syringae growth (MIC ~ 500 μg/mL), but not at concentrations found in IWFs, and DHCA did not inhibit biofilm formation in vitro. However, infiltration of exogenous DHCA enhanced resistance in mature cyp71a12/cyp71a13. These results provide evidence that DHCA derived from CYP71A12 and CYP71A13 activity accumulates in the intercellular space and contributes to the resistance of mature Arabidopsis to P. syringae without directly inhibiting bacterial growth.
- Kempthorne, Christine J.,Nielsen, Alexander J.,Wilson, Daniel C.,McNulty, James,Cameron, Robin K.,Liscombe, David K.
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- Condensation of 2-((Alkylthio)(aryl)methylene)malononitrile with 1,2-Aminothiol as a Novel Bioorthogonal Reaction for Site-Specific Protein Modification and Peptide Cyclization
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Site-specific modification of peptides and proteins has wide applications in probing and perturbing biological systems. Herein we report that 1,2-aminothiol can react rapidly, specifically and efficiently with 2-((alkylthio)(aryl)methylene)malononitrile (TAMM) under biocompatible conditions. This reaction undergoes a unique mechanism involving thiol-vinyl sulfide exchange, cyclization, and elimination of dicyanomethanide to form 2-aryl-4,5-dihydrothiazole (ADT) as a stable product. An 1,2-aminothiol functionality can be introduced into a peptide or a protein as an N-terminal cysteine or an unnatural amino acid. The bioorthogonality of this reaction was demonstrated by site-specific labeling of not only synthetic peptides and a purified recombinant protein but also proteins on mammalian cells and phages. Unlike other reagents in bioorthogonal reactions, the chemical and physical properties of TAMM can be easily tuned. TAMM can also be applied to generate phage-based ADT-cyclic peptide libraries without reducing phage infectivity. Using this approach, we identified ADT-cyclic peptides with high affinity to different protein targets, providing valuable tools for biological studies and potential therapeutics. Furthermore, the mild reaction conditions of TAMM condensation warrant its use with other bioorthogonal reactions to simultaneously achieve multiple site-specific modifications.
- Gao, Wei,Li, Xuefei,Li, Zhuoru,Luk, Louis Y. P.,Meng, Xiaoting,Tsai, Yu-Hsuan,Wu, Chuanliu,Zhao, Yibing,Zheng, Xiaoli
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- Synthesis method of thiazoline heterocyclic compound and application of thiazoline heterocyclic compound in biomolecular modification
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The invention discloses a synthesis method of a thiazoline heterocyclic compound and application of the thiazoline heterocyclic compound in biomolecular modification, and relates to the technical field of organic synthesis. The synthesis method comprises the following steps: mixing a thioalkene ether compound and a compound containing a 1, 2-mercaptoethylamine skeleton structure in a solvent, andadding a weak base to react for 60-240 minutes at the reaction temperature of 20-60 DEG C to obtain the dihydrothiazole heterocyclic compound. The synthesis method of the thiazolidine heterocyclic compound is mild and efficient, can quickly react in water at room temperature, and overcomes the defects of violent reaction conditions, long reaction time and the like in the traditional synthetic method; by means of the synthesis method, biomolecules such as polypeptide and protein containing the nitrogen-terminal cysteine residues can be efficiently and accurately modified, and application of detection and treatment methods and the like is further developed.
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- Synthesis, biological activities, and 3D-QSAR studies of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfonohydrazide moiety
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To discover a novel lead structure for antiphytopathogenic fungus agent, a series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfonohydrazide moiety were designed and synthesized. They were determined by melting points, 1H NMR, 13C NMR, and elemental analysis (EA). The biological activity results revealed that these title compounds possessed antifungal and insecticidal activities. Some title compounds against Alternaria solani, Physalospora piricola, Cercospora arachidicola, Phytophthora capsici, Fusarium graminearum, and Sclerotinia sclerotiorum displayed moderate to good antifungal activities at 50 mg/L, especially, compounds 6b and 6p displayed good and broad-spectrum antifungal activities. The structure activity relationships were discussed. A 3D-QSAR model was established based on the antifungal activity against Phytophthora capsici, indicating that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. Hence, structure optimization based on the CoMSIA model was performed to find compound 6p with excellent activity against Phytophthora capsici, and the EC50 values of compound 6p were comparable to those of chlorothalonil. Furthermore, the insecticidal activity of compound 6p against Culex pipiens larvae at 1 mg/L was considerable to that of chlorantraniliprole. Therefore, compound 6p can be used as a novel lead structure for antiphytopathogenic fungus and insecticidal agent development.
- Li, Fengyun,Li, Yuxin,Li, Zhengming,Liu, Jingbo,Wang, Yuanhong,Zhang, Haoxuan
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- Synthesis, biological activities and 3D-QSAR studies of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety
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A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety were synthesized and characterized on the basis of NMR and elemental analysis (EA). The crystal structure of (R)-N-(2-methyl-1-(methylthio)propan-2-yl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carboxamide (13d) was determined to show R configuration. The bioasssy results indicated that most title compounds displayed good and broad spectrum antifungal activities against several phytopathogenic fungi. The structure activity relationships were discussed. Based on the antifungal activity of title compounds against Phytophthora capsici, a CoMSIA calculation was performed to establish a 3D-QSAR model, which revealed that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. According to the established 3D-QSAR model, structure optimization was carried out to find (R)-N-((R)-1-(methylthio)propan-2-yl)-2-(p-tolyl)-4,5-dihydrothiazole-4-carboxamide (15h) with excellent activity against Phytophthora capsici, thus emerging as a new lead compound for novel antiphytopathogenic fungus agent development.
- Liu, Jingbo,Li, Fengyun,Wang, Yuanhong,Zhang, Haoxuan,Dong, Jingyue,Sun, Pengwei,Li, Yuxin,Li, Zhengming
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supporting information
p. 668 - 671
(2018/11/27)
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- (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a diacylhydrazine group: Synthesis, biological evaluation, and SARs
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A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a diacylhydrazine moiety were designed and synthesized. Their structures were confirmed by melting points, 1H NMR, 13C NMR, and elemental analysis (EA). Their antifungal and insecticidal activities were evaluated. The antifungal activity result indicated that most title compounds against Cercospora arachidicola, Alternaria solani, Phytophthora capsici, and Physalospora piricola exhibited apparent antifungal activities at 50 mg/L, and better than chlorothalonil or carbendazim. The EC50 values of (R)-N'-benzoyl-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide (I-5) against six tested phytopathogenic fungi were comparable to those of chlorothalonil. The CoMSIA model showed that a proper hydrophilic group in the R1 position, as well as a proper hydrophilic and electron-donating group in the R2 position, could improve the antifungal activity against Physalospora piricola, which contributed to the further optimization of the structures. Meanwhile, most title compounds displayed good insecticidal activities, especially compound (R)-N'-(4-nitrobenzoyl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-3). The insecticidal mechanism results indicated that compound III-3 can serve as e_ective insect Ca2+ level modulators by disrupting the cellular calcium homeostasis in Mythimna separata.
- Li, Feng-Yun,Liu, Jing-Bo,Gong, Jia-Ning,Li, Gen
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- Cu(i)-Catalyzed oxidative homo-coupling of thiazoline-4-carboxylates: Synthesis of 4,4′-bithiazoline derivatives
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Cu(i)-Catalyzed oxidative homo-coupling of thiazoline-4-carboxylates with good functional group tolerance has been developed. The methodology presented an efficient method to directly construct vicinal carbon-hetero quaternary centers existing in numerous functional molecules and could be applied to the synthesis of 4,4′-bithiazoles which are difficult to prepare by direct C-H activation.
- Fang, Xinxin,Zhang, Kaifan,Yao, Hequan,Huang, Yue
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supporting information
p. 8030 - 8034
(2016/09/09)
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- Ruthenium(II) complexes derived from 2-phenylthiazoline-4-carboxylic acid: Structure and catalytic activity for transfer hydrogenation reaction
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Piano-stool ([(p-cymene)Ru(thz)Cl], 2) and six-coordinated ([Ru(thz)2(PPh3)2], 3) ruthenium complexes derived from 2-phenylthiazoline-4-carboxylic acid (Hthz, 1) were synthesized for the first time, and fully characterized using conventional methods. Also, the molecular structure of complex 3 was determined using X-ray analysis. These complexes were evaluated as catalysts for transfer hydrogenation of carbonyl compounds in the presence of isopropyl alcohol and KOtBu. Complex 2 was found to be more active than 3 in transfer hydrogenation.
- Denizalt, Serpil,G?ke, Ayta Gürhan,en, Betül,etinkaya, Bekir
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p. 373 - 377
(2016/05/02)
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- Synthesis of aryl dihydrothiazol acyl shikonin ester derivatives as anticancer agents through microtubule stabilization
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The high incidence of cancer and the side effects of traditional anticancer drugs motivate the search for new and more effective anticancer drugs. In this study, we synthesized 17 kinds of aryl dihydrothiazol acyl shikonin ester derivatives and evaluated their anticancer activity through MTT assay. Among them, C13 showed better antiproliferation activity with IC50 = 3.14 ± 0.21 μM against HeLa cells than shikonin (IC50 = 5.75 ± 0.47 μM). We then performed PI staining assay, cell cycle distribution, and cell apoptosis analysis for C13 and found that it can cause cell arrest in G2/M phase, which leads to cell apoptosis. This derivative can also reduce the adhesive ability of HeLa cells. Docking simulation and confocal microscopy assay results further indicated that C13 could bind well to the tubulin at paclitaxel binding site, leading to tubulin polymerization and mitotic disruption.
- Lin, Hong-Yan,Li, Zi-Kang,Bai, Li-Fei,Baloch, Shahla Karim,Wang, Fang,Qiu, Han-Yue,Wang, Xue,Qi, Jin-Liang,Yang, Raong-Wu,Wang, Xiao-Ming,Yang, Yong-Hua
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- Design and synthesis of new 2-aryl-4,5-dihydro-thiazole analogues: In vitro antibacterial activities and preliminary mechanism of action
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Sixty 2-aryl-4,5-dihydrothiazoles were designed and synthesized in yields ranging from 64% to 89% from cysteine and substituted-benzonitriles via a novel metal- and catalyst-free method. The structures of the title compounds were confirmed mainly by NMR spectral data analysis. Antibacterial activity assays showed that the compounds (S)-2-(2′-hydroxyphenyl)-4-hydroxy-methyl-4,5-dihydrothiazole (7h) and (R)-2-(2′-hydroxyphenyl)-4-hydroxymethyl-4,5-dihydro-thiazole (7h′) exhibited significant inhibition against Ralstonia solanacearum, Pseudomonas syringae pv. actinidiae, Bacillus subtilis and Bacillus cereus, with minimum inhibitory concentrations (MICs) ranging from 3.91 to 31.24 μg·mL-1. The effect of substituents showed that not only electron-withdrawing groups, but also electron-donating groups could abolish the antibacterial activities unless a 2′-hydroxy group was introduced on the 2-aryl substituent of the 4,5-dihydrothiazole analogues. The results of scanning electron microscope (SEM) and fatty acid exposure experiments indicated that these antibacterial compounds influence fatty acid synthesis in the tested bacteria.
- Tan, Fangfang,Shi, Baojun,Li, Jian,Wu, Wenjun,Zhang, Jiwen
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p. 20118 - 20130
(2015/12/23)
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- Design, Synthesis, Antifungal Activities and SARs of (R)-2-Aryl-4,5-dihydrothiazole-4-carboxylic Acid Derivatives
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Based on the structure of natural product 2-aryl-4,5-dihydrothiazole-4-carboxylic acid, a series of novel (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives were designed and synthesized. Their structures were characterized by 1H NMR, 13C NMR and HRMS. The single crystal structure of compound 9b was determined by X-ray diffraction analysis. The antifungal activities were evaluated for the first time. The bioassay results indicated that most compounds exhibited moderate to good antifungal activities. The antifungal activities of compound 13a (against Cercospora arachidicola Hori), 13d (against Alternaria solani), and 16e (against Cercospora arachidicola Hori) were 61.9%, 67.3% and 61.9%, respectively, which are higher than those of the commercial fungicides chlorothalonil and carbendazim. Moreover, compound 13d exhibited excellent antifungal activities against 7 kinds of the fungi tested (66.7%, 77.3%, 63.0%, 87.9%, 70.0%, 70.0% and 80.0% at 50 μg?mL). Therefore, 13d can be used as a new lead structure for the development of antifungal agents.
- Liu, Jingbo,Li, Yuxin,Chen, Youwei,Hua, Xuewen,Wan, Yingying,Wei, Wei,Song, Haibin,Yu, Shujing,Zhang, Xiao,Li, Zhengming
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p. 1269 - 1275
(2015/11/27)
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- Semi-synthesis and anti-lung cancer activity evaluation of aryl dihydrothiazol acyl podophyllotoxin ester derivatives
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Lung cancer is the leading cause of cancer death worldwide, making it one of the biggest concerns for chemoprevention. In this study, we obtained seventeen potent anticancer agents through semi-synthesis based on a natural product, podophyllotoxin. Despite prior studies of podophyllotoxin derivatives being focussed on DNA-topoisomerase II, we now turn our attention to their effect on tubulin. The MTT assay screened out the most potent anticancer agent, S12 (IC50 = 0.18 μM against A549 cell line), and it showed lower cytotoxicity against normal cells. Next, the flow cytometry analysis result demonstrated that it can cause a remarkable cell cycle arrest at G2/M phase but the effect on apoptosis is not very significant. In addition, docking simulation results showed that S12 can nicely bound to the colchicine binding site of tubulin. Furthermore, we confirmed that S12 can really inhibit tubulin polymerization through confocal microscopy and protein expression determination assay.
- Lin, Hong-Yan,Bai, Li-Fei,Wang, Fang,Wu, Xun,Han, Lu-Jing,Baloch, Shahla Karim,Yang, Yong-Hua,Wang, Xiao-Ming
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p. 27775 - 27784
(2015/03/31)
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- Stereoselective synthesis of lanthionine derivatives in aqueous solution and their incorporation into the peptidoglycan of Escherichia coli
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The three diastereoisomers - (R,R), (S,S) and meso - of lanthionine were synthesized in aqueous solution with high diastereoselectivity (>99%). The (S) and (R) enantiomers of two differently protected sulfamidates were opened by nucleophilic attack of (R) or (S)-cysteine. Acidification and controlled heating liberated the free lanthionines. Using the same chemistry, an α-benzyl lanthionine was also prepared. The proposed method, which avoids the need of enrichment by recrystallization, opens the way to the labelling of these compounds with 35S. Furthermore, in vivo bioincorporation into Escherichia coli W7 was studied. No incorporation of α-benzyl lanthionine was observed. In contrast, meso-lanthionine can effectively replace meso-diaminopimelic acid in vivo, while in the presence of (R,R)-lanthionine the initial increase of bacterial growth was followed by cell lysis. In the future, meso-[35S]lanthionine could be used to study the biosynthesis of peptidoglycan and its turnover in relation to cell growth and division.
- Denoel, Thibaut,Zervosen, Astrid,Gerards, Thomas,Lemaire, Christian,Joris, Bernard,Blanot, Didier,Luxen, Andre
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p. 4621 - 4628
(2014/10/16)
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- Predicting the reactivity of nitrile-carrying compounds with cysteine: A combined computational and experimental study
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Here, we report on a mechanistic investigation based on DFT calculations and kinetic measures aimed at determining the energetics related to the cysteine nucleophilic attack on nitrile-carrying compounds. Activation energies were found to correlate well with experimental kinetic measures of reactivity with cysteine in phosphate buffer. The agreement between computations and experiments points to this DFT-based approach as a tool for predicting both nitrile reactivity toward cysteines and the toxicity of nitriles as electrophile agents.
- Berteotti, Anna,Vacondio, Federica,Lodola, Alessio,Bassi, Michele,Silva, Claudia,Mor, Marco,Cavalli, Andrea
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supporting information
p. 501 - 505
(2014/06/09)
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- Highly practical synthesis of nitriles and heterocycles from alcohols under mild conditions by aerobic double dehydrogenative catalysis
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A mild, aerobic, catalytic process for obtaining nitriles directly from alcohols and aqueous ammonia is described. The reaction proceeds via a dehydrogenation cascade mediated by catalytic CuI, bpy, and TEMPO in the presence of O2. The substrate scope is broad including various functionalized aromatic and aliphatic alcohols. This protocol enabled the one-pot synthesis of various biaryl heterocycles directly from commercially available alcohols.
- Yin, Weiyu,Wang, Chengming,Huang, Yong
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p. 1850 - 1853
(2013/06/04)
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- Medium buffer effects on the condensation of l -cysteine and aryl nitriles to (R)-2-Aryl-4,5-dihydrothiazole-4-carboxylic acids
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The condensation of l-cysteine and aryl nitriles to (R)-2-aryl-4,5- dihydrothiazole-4-carboxylic acids in buffered media was reinvestigated. Pure products (yields of 58-95%; up to 99% ee) were obtained in a NaHCO 3/NaOH-buffered aqueous alcoholic medium. Georg Thieme Verlag Stuttgart New York.
- Maltsev, Oleg V.,Walter, Valerianne,Brandl, Matthias J.,Hintermann, Lukas
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p. 2763 - 2767
(2013/10/21)
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- Generation and exploration of new classes of antitubercular agents: The optimization of oxazolines, oxazoles, thiazolines, thiazoles to imidazo[1,2-a]pyridines and isomeric 5,6-fused scaffolds
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Tuberculosis (TB) is a devastating disease resulting in a death every 20 s. Thus, new drugs are urgently needed. Herein we report ten classes of compounds - oxazoline, oxazole, thiazoline, thiazole, pyrazole, pyridine, isoxazole, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and imidazo[1,2-c]pyrimidine - which have good (micromolar) to excellent (sub-micromolar) antitubercular potency. The 5,6-fused heteroaromatic compounds were the most potent with MIC's as low as 37Rv, clinically relevant drug sensitive, multi- and extensively resistant Mtb strains as well as having good in vitro metabolic stability.
- Moraski, Garrett C.,Markley, Lowell D.,Chang, Mayland,Cho, Sanghyun,Franzblau, Scott G.,Hwang, Chang Hwa,Boshoff, Helena,Miller, Marvin J.
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supporting information; experimental part
p. 2214 - 2220
(2012/05/20)
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- 2-Substituted 4,5-dihydrothiazole-4-carboxylic acids are novel inhibitors of metallo-β-lactamases
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Bacterial resistance to β-lactam antibiotics caused by class B metallo-β-lactamases (MBL), especially for certain hospital-acquired, Gram-negative pathogens, poses a significant threat to public health. We report several 2-substituted 4,5-dihydrothiazole-4-carboxylic acids to be novel MBL inhibitors. Structure activity relationship (SAR) and molecular modeling studies were performed and implications for further inhibitor design are discussed.
- Chen, Pinhong,Horton, Lori B.,Mikulski, Rose L.,Deng, Lisheng,Sundriyal, Sandeep,Palzkill, Timothy,Song, Yongcheng
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supporting information
p. 6229 - 6232
(2012/10/29)
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- Pd(ii)-catalyzed direct C5-arylation of azole-4-carboxylates through double C-H bond cleavage
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The first palladium-catalyzed direct C5-arylation of azole-4-carboxylates with simple unactivated arenes through double C-H bond cleavage is realized. This protocol provided a straightforward access to diverse 5-arylsubstituted azole-4-carboxylic derivatives with good functional group tolerance. The Royal Society of Chemistry 2012.
- Li, Ziyuan,Ma, Ling,Xu, Jinyi,Kong, Lingyi,Wu, Xiaoming,Yao, Hequan
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p. 3763 - 3765
(2012/06/15)
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- Copper-catalyzed oxidation of azolines to azoles
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We report herein convenient, aerobic conditions for the oxidation of thiazolines to thiazoles and data regarding the oxidation mechanism. These reactions feature operationally simple and environmentally benign conditions and proceed in good yield to afford the corresponding azoles, thus enabling the inexpensive preparation of valuable molecular building blocks. Incorporation of a novel diimine-ligated copper catalyst, [(MesDABMe) CuII(OH2)3]2+ [-OTf] 2, provides increased reaction efficiency in many cases. In other cases copper-free conditions involving a stoichiometric quantity of base affords superior results.
- Dawsey, Anna C.,Li, Vincent,Hamilton, Kimberly C.,Wang, Jianmei,Williams, Travis J.
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supporting information; experimental part
p. 7994 - 8002
(2012/08/08)
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- Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl- thiazoles analogues as potent and orally bioavailable anticancer agents
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In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-aryl-thiazole (SMART) template, we explored chemodiverse "B" rings and "B" to "C" ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-amino-thiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between "A" and "B" rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45a-c (PAT) vs 1 (SMART)).
- Lu, Yan,Li, Chien-Ming,Wang, Zhao,Chen, Jianjun,Mohler, Michael L.,Li, Wei,Dalton, James T.,Miller, Duane D.
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supporting information; experimental part
p. 4678 - 4693
(2011/09/14)
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- COMPOUNDS FOR TREATMENT OF CANCER
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The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.
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Paragraph 0036; 00291
(2011/10/03)
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- Synthesis, formulation and in vitro evaluation of a novel microtubule destabilizer, SMART-100
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A novel microtubule destabilizer, substituted methoxybenzoyl-ary-thiazole (SMART)-100, was synthesized, which showed good anticancer activity in HepG2 cells. SMART-100 was able to circumvent multidrug resistance (MDR) and effectively inhibited the growth of cell lines that overexpress P-glycoprotein (P-gp). SMART-100 inhibited P-gp activity, which may be responsible for its ability to overcome MDR. Since SMART-100 is poorly soluble in water, it was formulated in polyethylene-b-poly(d,l-lactide) (PEG-PLA) micelles. The solubility of SMART-100 was increased by more than 1.1×105 folds. SMART-100 loaded PEG-PLA micelles could effectively inhibit HepG2 cell growth and arrest cell cycle progression at G2/M phase, followed by appearance of a sub-G1 phase, which is indicative of cell apoptosis. Increased Caspase-3 activity was also observed when HepG2 cells were treated with SMART-100. The anticancer activity of SMART-100 loaded PEG-PLA micelles was also evaluated on luciferase expressing C4-2-Luc cell lines by IVIS imaging. Our results suggest that SMART-100 has the potential to treat resistant cancers.
- Li, Feng,Lu, Yan,Li, Wei,Miller, Duane D.,Mahato, Ram I.
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experimental part
p. 151 - 158
(2011/05/04)
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- Discovery of 4-substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: Synthesis, biological evaluation, and structure-activity relationships
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A series of 4-substituted methoxybenzoyl-aryl-thiazoles (SMART) have been discovered and synthesized as a result of structural modifications of the lead compound 2-arylthiazolidine-4-carboxylic acid amides (ATCAA). The antiproliferative activity of the SMART agents against melanoma and prostate cancer cells was improved from μM to low nM range compared with the ATCAA series. The structure-activity relationship was discussed from modifications of "A", "B", and "C" rings and the linker. Preliminary mechanism of action studies indicated that these compounds exert their anticancer activity through inhibition of tubulin polymerization.
- Lu, Yan,Li, Chien-Ming,Wang, Zhao,Ross, Charles R.,Chen, Jianjun,Dalton, James T.,Li, Wei,Miller, Duane D.
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experimental part
p. 1701 - 1711
(2010/01/16)
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- COMPOUNDS FOR TREATMENT OF CANCER
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Compounds according to formula (I) are disclosed where Q is S, N, or O; X is optional, and can be O═, S═, ═N—NH2, ═N—OH, or —OH; Y is optional and can be —N(H)—, O, or C1 to C20 hydrocarbon; and R1 and R2 are each independently substituted or unsubstituted single-, fused- or multiple-ring aryl or (hetero)cyclic ring systems. Methods of making these compounds, pharmaceutical compositions containing the compounds, and their use, particularly for treating or preventing cancer, are also disclosed.
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Page/Page column 13-14
(2010/01/31)
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- THIAZOLIDINONE AMIDES, THIAZOLIDINE CARBOXYLIC ACID AMIDES, AND SERINE AMIDES, INCLUDING POLYAMINE CONJUGATES THEREOF, AS SELECTIVE ANTI-CANCER AGENTS
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Substituted thiazolidinone carboxylic acid amides and substituted thiazolidine carboxylic acid amides having a structure where the various substituent groups are as defined in the specification. Methods of making these compounds, pharmaceutical compositions containing the compounds, and their use, particularly for treating or preventing cancer, are also disclosed.
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Page/Page column 5; sheet 8
(2008/12/04)
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- Synthesis and antiproliferative activity of thiazolidine analogs for melanoma
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We have previously described 2-aryl-thiazolidine-4-carboxylic acid amides as a novel class of antiproliferative agents for prostate cancer. Screening these compounds with melanoma cell lines revealed that several of them have potent antiproliferative activity and selectivity against melanoma. To further improve the potency and selectivity, we synthesized a new series of analogs and tested them in two melanoma cell lines and fibroblast cells (negative controls). Comparison of anticancer effects of these compounds with a standard chemotherapeutic agent, sorafenib, showed that they are very effective in killing melanoma cells with low micromolar to nanomolar antiproliferative activity and provide us a new lead for developing potential drugs for melanoma.
- Li, Wei,Lu, Yan,Wang, Zhao,Dalton, James T.,Miller, Duane D.
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p. 4113 - 4117
(2008/02/08)
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- PROCESS FOR PRODUCING OPTICALLY ACTIVE ALPHA-SUBSTITUTED CYSTEINE OR SALT THEREOF, INTERMEDIATE THEREFOR, AND PROCESS FOR PRODUCING THE SAME
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The present invention provides a simple, practical, and industrially advantageous process for producing an optically active α-substituted cysteine or a salt thereof from inexpensive and readily available materials.The present invention provides a process for producing an optically active α-substituted cysteine or a salt thereof by converting a cysteine derivative into a thiazoline compound and subjecting the resulting thiazoline compound to a stereoselective substituent-introducing reaction catalyzed by an optically active quaternary ammonium salt, in particular, an axially asymmetric quaternary ammonium salt to produce an optically active thiazoline compound and then hydrolyzing the resulting thiazoline compound.
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Page/Page column 11
(2008/06/13)
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- Amino Acids, 12. - Syntheses of DL-Cysteines from Acrylic Acid Derivatives
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The addition of sulfenyl chlorides 1 to 2-alkenoic acid esters 2 gives mixtures of 2(3)-chloro-3(2)-thioalkenoic acid esters 3/4, whereas the addition of thiols 7 to methyl 2-chloro-2-propenoate (6) results in the formation of methyl 2-chloro-3-thiopropanoates 3 only.The dependence of the isomerization of 3 to 4 on the reaction conditions was investigated; at higher temperatures the formation of 4 is especially favored.At temperatures below 55 deg C the 2-azido compounds 8 are obtained without isomerization from 3 by reaction with sodium azide in the presence of a PT catalyst.Cysteine derivatives 9 or 10, resp., are obtained by hydrogenation of 8 with H2S/pyridine/H2O or with H2/Re2S; the overall yields of 9 or 10, resp., starting from 6 are as high as 70percent.DL-Cysteine is obtained in good overall yields as hydrochloride hydrate 16 by HCl-catalyzed hydrolysis of the 2-thiazolines 15a*HCl and 15e, which are prepared by HCl-catalyzed addition of thioacetamide (11a) to α-chloroacrylic acid (12) or the amide 13 and consecutive ring closure.
- Effenberger, Franz,Beisswenger, Thomas,Dannenhauer, Fritz
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p. 2209 - 2224
(2007/10/02)
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- Synthesis and Nuclear Magnetic Resonance Study of 2-Thiazolines
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A series of 5,5-dimethyl-2-thiazoline-4-carboxylates with a phenyl or methyl group at the 2-position of the ring were prepared from the corresponding methyl or ethyl ester of penicillamine and either methyl benzimidate or ethyl acetimidate.The free acid was obtained by the reaction of penicillamine with benzonitrile to produce 5,5-dimethyl-2-phenyl-2-thiazoline-4-carboxylic acid.Corresponding thiazolines were prepared from cysteine in the same manner.The nuclear magnetic resonance spectra of both series exhibit coupling of the methyl group at the 2-position with the hydrogen at the 4-position.The groups at the 5-position are nonequivalent and in the case of the cysteine series give rise to an ABX system.Further analysis confirms a concentration dependence for this splitting pattern.
- Eggleton, Gordon L.,Bushman, Daniel R.,Whitlock, David W.,Pugh, Darrell K.,Chance, Katherine L.
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p. 351 - 354
(2007/10/02)
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