- Study of the interaction between sodium salts of (2E)-3-(4'-halophenyl) prop-2-enoyl sulfachloropyrazine and bovine serum albumin by fluorescence spectroscopy
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Three sodium salts of (2E)-3-(4'-halophenyl)prop-2-enoyl sulfachloropyrazine (CCSCP) were synthesized and their structures were determined by 1H and 13C NMR, LC-MS and IR. The binding properties between CCSCPs and bovine serum albumi
- Luo, Xuan,Du, Chuanrong,Wei, Jinrui,Deng, Jiang,Lin, Yijie,Lin, Cuiwu
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Read Online
- Evaluation of achiral templates with fluxional bronsted basic substituents in enantioselective conjugate additions
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Enantioselective conjugate addition of malononitrile to pyrazolidinone-derived enoates proceeds in excellent yields and high enantioselectivities. A comparison of fluxional substituents with and without a Bronsted basic site and their impact on selectivity is detailed. Molecular sieves as an additive were found to be essential to achieve high enantioselectivity.
- Adachi, Shinya,Takeda, Norihiko,Sibi, Mukund P.
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Read Online
- Design, Synthesis, and Anticancer Activity of Cinnamoylated Barbituric Acid Derivatives
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This work deals with the design and synthesis of 18 barbituric acid derivatives bearing 1,3-dimethylbarbituric acid and cinnamic acid scaffolds to find potent anticancer agents. The target molecules were obtained through Knoevenagel condensation and acylation reaction. The cytotoxicity was assessed by the MTT assay. Flowcytometry was performed to determine the cell cycle arrest, apoptosis, ROS levels and the loss of MMP. The ratios of GSH/GSSG and the MDA levels were determined by using UV spectrophotometry. The results revealed that introducing substitutions (CF3, OCF3, F) on the meta- of the benzyl ring of barbituric acid derivatives led to a considerable increase in the antiproliferative activities compared with that of corresponding ortho- and para-substituted barbituric acid derivatives. Mechanism investigation implied that the 1c could increase the ROS and MDA level, decrease the ratio of GSH/GSSG and MMP, and lead to cell cycle arrest. Further research is needed for structural optimization to enhance hydrophilicity, thereby improve the biological activity of these compounds.
- Liu, Yue,Li, Peng-Xiao,Mu, Wen-Wen,Sun, Ya-Lei,Liu, Ren-Min,Yang, Jie,Liu, Guo-Yun
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- Synthesis of sorbicillinoid analogues with anti-inflammation activities
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Recently, we demonstrated potential anti-inflammatory effects of sorbicillinoids isolated from marine fungi. Here, we report the synthesis of a series of new sorbicillinoid analogues and assessed their anti-inflammatory activities. Our results reveal that side chain substitution with (E)-2-butenoyl, (E)-3-(4-fluorophenyl)-2-propenoyl, and (E)-3-(3,4,5-trimethoxyphenyl)-2-propenoyl significantly enhanced the inhibitory effects of the derivatives on nitric oxide (NO) production and inducible NO synthesis (iNOS) expression stimulated by lipopolysaccharides (LPS) in mouse macrophage. Further chemical derivatization shows that the monomethylresorcinol skeleton worked better than the dimethylresorcinol skeleton in inhibiting LPS-induced inflammatory response in cultured cells. Among the 29 synthesized sorbicillinoid analogues, compounds 4b and 12b exhibited the strongest anti-inflammatory activities, holding the promise of being developed into lead compounds that can be explored as potent anti-inflammation agents.
- Zhang, Meng,Wang, Fangfang,Ding, Wenjuan,Xu, Zhipeng,Li, Xiaosan,Tian, Danmei,Zhang, Youwei,Tang, Jinshan
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- Photoredox Cyclization of N-Arylacrylamides for Synthesis of Dihydroquinolinones
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Metal- and additive-free photoredox cyclization of N-arylacrylamides is herein reported that provides a concise access to the formation of dihydroquinolinones. In this protocol, sustainable visible light was used as the energy source, and the organic light-emitting molecule 4CzIPN served as the efficient photocatalyst. This reaction system features exclusive 6-endo-trig cyclization selectivity with a generally good yield of a range of functionalized dihydroquinolinones and dihydrobenzoquinolinones. Mechanistical studies reveal the feasibility of both 1,3-H shift and intersystem crossing of the diradical intermediate.
- Liu, Zhaosheng,Zhong, Shuai,Ji, Xiaochen,Deng, Guo-Jun,Huang, Huawen
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supporting information
p. 349 - 353
(2021/12/27)
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- Quorum sensing and nf-κb inhibition of synthetic coumaperine derivatives from piper nigrum
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Bacterial communication, termed Quorum Sensing (QS), is a promising target for virulence attenuation and the treatment of bacterial infections. Infections cause inflammation, a process regulated by a number of cellular factors, including the transcription Nuclear Factor kappa B (NF-κB); this factor is found to be upregulated in many inflammatory diseases, including those induced by bacterial infection. In this study, we tested 32 synthetic derivatives of coumaperine (CP), a known natural compound found in pepper (Piper nigrum), for Quorum Sensing Inhibition (QSI) and NF-κB inhibitory activities. Of the compounds tested, seven were found to have high QSI activity, three inhibited bacterial growth and five inhibited NF-κB. In addition, some of the CP compounds were active in more than one test. For example, compounds CP-286, CP-215 and CP-158 were not cytotoxic, inhibited NF-κB activation and QS but did not show antibacterial activity. CP-154 inhibited QS, decreased NF-κB activation and inhibited bacterial growth. Our results indicate that these synthetic molecules may provide a basis for further development of novel therapeutic agents against bacterial infections.
- Baruch, Yifat,Gopas, Jacob,Kadosh, Yael,Kumar, Rajendran Saravana,Kushmaro, Ariel,Muthuraman, Subramani,Yaniv, Karin
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- Piperlongumine analogs promote A549 cell apoptosis through enhancing ROS generation
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Chemotherapeutic agents, which contain the Michael acceptor, are potent anticancer molecules by promoting intracellular reactive oxygen species (ROS) generation. In this study, we synthesized a panel of PL (piperlongumine) analogs with chlorine attaching at C2 and an electronwithdrawing/electron-donating group attaching to the aromatic ring. The results displayed that the strong electrophilicity group at the C2–C3 double bond of PL analogs plays an important role in the cytotoxicity whereas the electric effect of substituents, which attached to the aromatic ring, partly contributed to the anticancer activity. Moreover, the protein containing sulfydryl or seleno, such as TrxR, could be irreversibly inhibited by the C2–C3 double bond of PL analogs, and boost intracellular ROS generation. Then, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death. In conclusion, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR and ROS accumulation.
- Li, Peng-Xiao,Li, Yan-Mo,Liu, Guo-Yun,Liu, Ren-Min,Mu, Wen-Wen,Sun, Ai-Ling,Sun, Ya-Lei,Yang, Jie
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- Cinnamyl-containing rupestonic acid methyl ester derivative as well as preparation method and application of rupestonic acid methyl ester derivative
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The invention relates to a cinnamyl-containing rupestonic acid methyl ester derivative as well as a preparation method and application thereof, the derivative is prepared by the following steps: reacting rupestonic acid with dimethyl sulfate to obtain rupestonic acid methyl ester, and then obtaining 2-hydroxyl rupestonic acid methyl ester under the oxidation of camphor sulfonyl acridine. and then reacting with cinnamyl chloride under the catalysis of DMAP to obtain 20 rupestonic acid methyl ester derivatives containing cinnamyl groups. The method has the advantages of mild reaction conditions and simple experimental steps. The obtained 1d-20d rupestonic acid methyl ester derivatives containing the cinnamyl groups are subjected to a preliminary in-vitro anti-influenza A H3N2 virus activity test. Experimental results show that the compounds show good activity in 7d, 15d and 18d, and can be used as drugs for resisting influenza A H3N2 virus.
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Paragraph 0119-0120; 0123
(2021/06/02)
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- Investigating the Role of Weak Interactions to Explore the Polymorphic Diversity in Difluorinated Isomeric N-Phenylcinnamamides
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A total of nine difluoro derivatives of N-phenylcinnamamides have been synthesized from fluoro-substituted cinnamic acids and anilines in order to investigate the formation of polymorphs arising due to the conformational flexibility around the amide and vinyl group. Among them, four compounds have been found to exist in multiple polymorphic forms, which includes concomitant polymorphism, solvatomorphism, and packing polymorphism, while the remaining five compounds display monomorphic behavior. Crystal structure analyses of all the forms belonging to these four compounds reveal that, although the molecules are primarily held by strong N-H?O hydrogen bonds, the relative interplay of weak C-H?F, C-H?O, C-H?π, and π?πinteractions allows the flexible molecules to adopt different orientations and exhibit polymorphism. These forms interestingly also display different thermal stabilities, and they have been quantified by intermolecular interaction topological analyses. The occurrence of different primary packing motifs in these crystal structures has been further investigated by the crystal structure prediction (CSP) computational method, wherein an energy landscape of an unsubstituted N-phenylcinnamamide was generated and a number of hypothetical structures were accessed with experimentally obtained crystal structures of its difluoro-substituted derivatives.
- Bhowal, Rohit,Chopra, Deepak
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p. 4162 - 4177
(2021/07/26)
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- Antifungal Exploration of Quinoline Derivatives against Phytopathogenic Fungi Inspired by Quinine Alkaloids
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Enlightened from our previous work of structural simplification of quinine and innovative application of natural products against phytopathogenic fungi, lead structure 2,8-bis(trifluoromethyl)-4-quinolinol (3) was selected to be a candidate and its diversified design, synthesis, and antifungal evaluation were carried out. All of the synthesized compounds Aa1-Db1 were evaluated for their antifungal activity against four agriculturally important fungi, Botrytis cinerea, Fusarium graminearum, Rhizoctonia solani, and Sclerotinia sclerotiorum. Results showed that compounds Ac3, Ac4, Ac7, Ac9, Ac12, Bb1, Bb10, Bb11, Bb13, Cb1. and Cb3 exhibited a good antifungal effect, especially Ac12 had the most potent activity with EC50 values of 0.52 and 0.50 μg/mL against S. sclerotiorum and B. cinerea, respectively, which were more potent than those of the lead compound 3 (1.72 and 1.89 μg/mL) and commercial fungicides azoxystrobin (both >30 μg/mL) and 8-hydroxyquinoline (2.12 and 5.28 μg/mL). Moreover, compound Ac12 displayed excellent in vivo antifungal activity, which was comparable in activity to the commercial fungicide boscalid. The preliminary mechanism revealed that compound Ac12 might cause an abnormal morphology of cell membranes, an increase in membrane permeability, and release of cellular contents. These results indicated that compound Ac12 displayed superior in vitro and in vivo fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.
- Chen, Yong-Jia,Ma, Kun-Yuan,Du, Sha-Sha,Zhang, Zhi-Jun,Wu, Tian-Lin,Sun, Yu,Liu, Ying-Qian,Yin, Xiao-Dan,Zhou, Rui,Yan, Yin-Fang,Wang, Ren-Xuan,He, Ying-Hui,Chu, Qing-Ru,Tang, Chen
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p. 12156 - 12170
(2021/10/26)
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- Design, Synthesis, Structure-Activity Relationship, Molecular Docking, and Herbicidal Evaluation of 2-Cinnamoyl-3-Hydroxycyclohex-2-en-1-one Derivatives as Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
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Cinnamic acid, isolated from cinnamon bark, is a natural product with excellent bioactivity, and it effectively binds with cyclohexanedione to form novel 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors. According to the active sub-structure combinat
- Song, Hao-Min,Zhao, Li-Xia,Zhang, Shuai-Qi,Ye, Tong,Fu, Ying,Ye, Fei
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p. 12621 - 12633
(2021/11/13)
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- Meta-substituted piperlongumine derivatives attenuate inflammation in both RAW264.7 macrophages and a mouse model of colitis
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Piperlongumine (PL) has been showed to have multiple pharmacological activities. In this study, we reported the synthesis of three series of PL derivatives, and evaluation of their anti-inflammatory effects in both lipopolysaccharide (LPS)-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. Our results presented that two meta-substituent containing derivatives 1–3 and 1–6, in which γ-butyrolactam replaced α,β-unsaturated δ-valerolactam ring of PL, displayed low cytotoxicity and effective anti-inflammatory activity. Molecular docking also showed that the meta-substituted derivative, compared with the corresponding ortho- or para-substituted derivative, had significant interactions with the amino acid residues of CD14, which was the core receptors recognizing LPS. In vitro and in vivo studies, 1–3 and 1–6 could inhibit the expression of pro-inflammatory cytokines, and the excessive production of reactive nitrogen species and reactive oxygen species. Oral administration of 100 mg/kg/day of 1–3 or 1–6 alleviated the severity of clinical symptoms of colitis in mice, and significantly reduced the colonic tissue damage to protect the colonic tissue from the DSS-induced colitis. These results suggested that meta-substituted derivatives 1–3 and 1–6 were potential anti-inflammatory agents, which may lead to future pharmaceutical development.
- Gong, Zhaotang,Liu, Guoyun,Mu, Wenwen,Wang, Ziqing,Yang, Jie
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- Practical access to fluorescent 2,3-naphthalimide derivatives: Via didehydro-Diels-Alder reaction
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A practical and efficient approach for the synthesis of fluorescent 2,3-naphthalimide derivatives has been developed from readily available starting materials via an intramolecular didehydro-Diels-Alder reaction, which proceeded well under room temperature, exhibiting a wide substrate scope and good functional group tolerance. The practicability of this methodology has been verified by one-step synthesis of the environmentally sensitive fluorophore 6-DMN on a gram scale with a shorter time, fewer steps and less waste disposal, and without the utilization of toxic transition metals. The present experimental and computational studies support the crucial role of the propiolimide moiety in the transformation.
- Chen, Xia,Zhong, Cheng,Lu, Yuling,Yao, Meng,Guan, Zhenhua,Chen, Chunmei,Zhu, Hucheng,Luo, Zengwei,Zhang, Yonghui
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supporting information
p. 5155 - 5158
(2021/05/31)
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- The potential role of the 5,6-dihydropyridin-2(1: H)-one unit of piperlongumine on the anticancer activity
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Piperlongumine (PL), a potent anticancer agent from the plant long pepper (Piper longum), contains the 5,6-dihydropyridin-2(1H)-one heterocyclic scaffold and cinnamoyl unit. In this paper, we synthesized a series of PL analogs and evaluated their cytotoxicity against cancer cells for the sake of exploring which pharmacophore plays a more potent role in enhancing the anticancer activities of PL. These results illustrated that the position effect, not the electronic effect, of substituents plays a certain role in the cytotoxicity of PL and its analogs. More important, the 5,6-dihydropyridin-2(1H)-one unit, a potent pharmacophore in enhancing the antiproliferative activities of PL, could react with cysteamine and lead to ROS generation, and then bring about the occurrence of ROS-induced downstream events, followed by cell cycle arrest and apoptosis. This work suggests that introducing a lactam unit containing Michael acceptors may be a potent strategy to enhancing the anticancer activity of drugs. This journal is
- Li, Peng-Xiao,Liu, Guo-Yun,Liu, Yue,Mu, Wen-Wen,Yang, Jie
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p. 42128 - 42136
(2020/12/09)
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- Synthesis and biological evaluation of coumarin derivatives as α-glucosidase inhibitors
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In this study, two series of coumarin derivatives 5a~i and 6a~i were synthesized, and their inhibitory activity against α-glucosidase was determined. The results indicated that most of the synthesized derivatives exhibited prominent inhibitory activities
- Chen, Jie,Chen, Wen-Hua,Deng, Xu-Yang,Jiang, Zheng-Yun,Li, Dong-Li,Liang, Qi-Ming,Ma, Ai-Jun,Wang, Shao-Hua,Wu, Pan-Pan,Xu, Xue-Tao,Zhang, Kun,Zheng, Xi,Zhou, Ren-Ping
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- New coumarin/sulfocoumarin linked phenylacrylamides as selective transmembrane carbonic anhydrase inhibitors: Synthesis and in-vitro biological evaluation
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Two novel series of phenylacrylamide linked coumarins and sulfocoumarins (6a-p, 8a-i, and 14a-g) were synthesized and evaluated against four physiologically relevant human carbonic anhydrases (hCAs, EC 4.2.1.1), isoforms hCA I, hCA II, hCA IX and hCA XII for their inhibitory action. All new compounds when screened for carbonic anhydrase inhibitory activity have shown selective inhibition towards the tumor associated isoforms hCA IX and XII over CA I and II, with inhibition constants in the submicromolar to low nanomolar range. Compound 6b and 14g exhibited significant inhibition with low nanomolar potency against hCA IX, whereas 6k was effective against hCA XII. Compounds 6b, 14g and 6k may be considered as lead molecules for future development of cancer therapeutics based on a novel mechanism of action.
- Angeli, Andrea,Arifuddin, Mohammed,Singh, Priti,Supuran, Claudiu T.,Swain, Baijayantimala
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- Coumarin derivative as well as preparation method and application thereof
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The invention discloses a coumarin derivative as well as a preparation method and application thereof. The chemical structural formula of the coumarin derivative is represented by a formula (I) or a formula (II), wherein in the formula, R1 is H, CH3, OCH3
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Paragraph 0043-0045
(2020/05/05)
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- Mild, Metal-Free and Protection-Free Transamidation of N-Acyl-2-piperidones to Amino Acids, Amino Alcohols and Aliphatic Amines and Esterification of N-Acyl-2-piperidones
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Amides are indispensable building blocks of biological systems, pharmaceuticals, and materials. We report a highly selective method for the synthesis of amides via transamidation process. Transamidation of N-acyl-2-piperidones with a broad range of amines is demonstrated under exceedingly mild and metal-free reaction condition that relies on the amide bond twist to weaken the amidic resonance. Transamidation proceeds under the neat condition at room temperature, in short reaction times (30–90 min) with good yields. Considerable variation is tolerated with both amine and imide substrates. Of note, amines bearing carboxylic acids (glycine and serine) and hydroxyl groups (dopamine, tyramine, etc.) are well tolerated which are otherwise problematic under the metal-catalyzed protocol. Our current method is applicable for transamidation of both alkyl and aryl-N-acyl-2-piperidones. The practical value of the method is highlighted by the synthesis of four natural product amide alkaloids in high yields under mild reaction conditions. In the absence of nucleophilic amines, N-acyl-2-piperidones undergoes esterification with EtOH at elevated temperature. Single crystal X-ray analysis of an N-acyl-2-piperidone shows amide bond twist, τ = –20.39° and pyramidalization, χN = –11.73°. This weakens the amidic conjugation and might be the factor controlling the reactivity and selectivity of these imides. We envision that the N-acyl-2-piperidone scaffold would be useful in the synthesis of pharmaceuticals and materials.
- Subramani, Muthuraman,Rajendran, Saravana Kumar
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p. 3677 - 3686
(2019/06/08)
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- Structure–activity study of fluorine or chlorine-substituted cinnamic acid derivatives with tertiary amine side chain in acetylcholinesterase and butyrylcholinesterase inhibition
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In this study, a series of new fluorine or chlorine-substituted cinnamic acid derivatives that contain tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The resu
- Gao, Xiao-Hui,Tang, Jing-Jing,Liu, Hao-Ran,Liu, Lin-Bo,Liu, Ying-Zi
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p. 438 - 445
(2019/02/01)
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- Design and synthesis novel di-carbonyl analogs of curcumin (DACs) act as potent anti-inflammatory agents against LPS-induced acute lung injury (ALI)
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A novel series of di-carbonyl analogs of curcumin (DACs) were prepared and evaluated for their anti-inflammatory properties. Preliminary results showed that a vast majority of compounds tested in this study could effectively suppress LPS-induced production of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Structure-activity relationships of the compounds were discussed. Compounds 5a27 and 5a28 showed the most potent anti-inflammatory activities and had higher structural stability and orally bioavailability than curcumin in vitro. Mechanistically, they inhibited the activation of macrophages via the blockade of mitogen-activated protein kinase (MAPK) signaling and nuclear translocation of NF-κB. In vivo, 5a27 and 5a28 markedly alleviated lipopolysaccharides (LPS)-induced acute lung injury (ALI). The wet/dry ratio of lungs was significantly normalized by the active compounds, which was consistent with the suppression of neutrophil infiltration and production of proinflammatory cytokines. Collectively, these results present a new series of curcumin analogs as promising anti-inflammatory agents for treatment of ALI.
- Qian, Jianchang,Chen, Xianxin,Shu, Sheng,Zhang, Wenxin,Fang, Bo,Chen, Xiaojing,Zhao, Yunjie,Liu, Zhiguo,Liang, Guang
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p. 414 - 425
(2019/02/19)
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- Activity-based protein profiling reveals GSTO1 as the covalent target of piperlongumine and a promising target for combination therapy for cancer
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Through systematic target identification for piperlongumine, a cancer-selective killing molecule, we identified GSTO1 as its major covalent target for cancer cell death induction. We also reveal that GSTO1 inhibition is a promising combination strategy with other anti-cancer agents by drug combination screening in which piperlongumine exhibits broad-spectrum synergistic effects with a large proportion of the tested anti-cancer agents, especially with PI3K/Akt/mTOR pathway inhibitors.
- Li, Li,Zhao, Yue,Cao, Ran,Li, Lin,Cai, Gaihong,Li, Jiaojiao,Qi, Xiangbing,Chen, She,Zhang, Zhiyuan
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supporting information
p. 4407 - 4410
(2019/04/26)
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- Synthesis and biological evaluation of celastrol derivatives as anti-ovarian cancer stem cell agents
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Ovarian cancer is associated with a high percentage of recurrence of tumors and resistance to chemotherapy. Cancer stem cells (CSCs) are responsible for cancer progression, tumor recurrence, metastasis, and chemoresistance. Thus, developing CSC-targeting therapy is an urgent need in cancer research and clinical application. In an attempt to achieve potent and selective anti-CSC agents, a series of celastrol derivatives with cinnamamide chains were synthesized and evaluated for their anti-ovarian cancer activities. Most of the compounds exhibited stronger antiproliferative activity than celastrol, and celastrol derivative 7g with a 3,4,5-trimethoxycinnamamide side chain was found to be the most potent antiproliferative agent against ovarian cancer cells with an IC50 value of 0.6 μM. Additionally, compound 7g significantly inhibited the colony formation ability and reduced the number of tumor spheres. Furthermore, compound 7g decreased the percentage of CD44+, CD133+ and ALDH+ cells. Thus, compound 7g is a promising anti-CSC agent and could serve as a candidate for the development of new anti-ovarian cancer drugs.
- Li, Xiaojing,Ding, Jie,Li, Ning,Liu, Wenxia,Ding,Zheng, Huijuan,Ning, Yanyan,Wang, Hongmin,Liu, Renmin,Ren, Shaoda
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p. 667 - 679
(2019/07/05)
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- Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors
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A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.
- Gao, Cheng-Zhi,Dong, Wei,Cui, Zhi-Wen,Yuan, Qiong,Hu, Xia-Min,Wu, Qing-Ming,Han, Xianlin,Xu, Yao,Min, Zhen-Li
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p. 150 - 162
(2018/11/30)
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- Pyridazinone derivative, and preparation method and medical application thereof
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The invention provides a pyridazinone derivative, and a preparation method and a medical application thereof. O-formylbenzoic acid used as a raw material reacts with dimethyl phosphite to obtain dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate, the dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate reacts with 3-cyano-4-fluorobenzaldehyde in the presence of triethylamine to prepare (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile, and the (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile is reduced by hydrazine hydrate to prepare 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid; and benzaldehyde or substituted aromatic formaldehyde or furfural used as a raw material and malonic acid undergo a Knoevenagel reaction to obtain cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid, the cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid and 1-tert-butoxycarbonylpiperazine undergo an amidation reaction, a tert-butoxycarbonyl group is removed from the obtained amidation product in the presence of trifluoroacetic acid, and the obtained product and the 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid undergo the amidation reaction to obtain a series of (E)-4-{3-[4-[(3-substituted aryl)acryloyl]piperazin-1-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one derivatives. Results of preliminary pharmacological activity screening show that the compound represented by a general formula shown in the present invention has a certain in-vitro PARP-1 inhibition ability and a certain in-vitro tumor cell proliferation resisting activity. The structural general formula of compound is shown in the description; and in the general formula, Ar is selected from two formulas also shown in the description, and R1, R2, R3, R3, R4 and R5 can be the hydrogen atom, the fluorine atom, the chlorine atom, the bromine atom, a methyl group, a methoxy group, a tetrafluoromethyl group and a nitro group.
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- N-Cinnamoylanthranilates as human TRPA1 modulators: Structure-activity relationships and channel binding sites
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The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel, which detects noxious stimuli leading to pain, itch and cough. However, the mechanism(s) of channel modulation by many of the known, non-reactive modulators has not been fully elucidated. N-Cinnamoylanthranilic acid derivatives (CADs) contain structural elements from the TRPA1 modulators cinnamaldehyde and flufenamic acid, so it was hypothesized that specific modulators could be found amongst them and more could be learnt about modulation of TRPA1 with these compounds. A series of CADs was therefore screened for agonism and antagonism in HEK293 cells stably transfected with WT-human (h)TRPA1, or C621A, F909A or F944A mutant hTRPA1. Derivatives with electron-withdrawing and/or electron-donating substituents were found to possess different activities. CADs with inductive electron-withdrawing groups were agonists with desensitising effects, and CADs with electron-donating groups were either partial agonists or antagonists. Site-directed mutagenesis revealed that the CADs do not undergo conjugate addition reaction with TRPA1, and that F944 is a key residue involved in the non-covalent modulation of TRPA1 by CADs, as well as many other structurally distinct non-reactive TRPA1 ligands already reported.
- Chandrabalan, Arundhasa,McPhillie, Martin J.,Morice, Alyn H.,Boa, Andrew N.,Sadofsky, Laura R.
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supporting information
p. 141 - 156
(2019/03/17)
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- PdII/Novel Chiral Cinchona Alkaloid Oxazoline-Catalyzed Enantioselective Oxidative Cyclization of Aromatic Alkenyl Amides
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A highly enantioselective PdII-catalyzed aza-Wacker oxidation tandem cyclization of aromatic nitrogen-containing dienes has been achieved in the presence of novel chiral cinchona alkaloid oxazoline ligands for the first time, affording chiral dihydroindole nitrogen-containing polycyclic compounds with good yields (up to 83 %), high diastereoselectivities (> 95:5 dr), and excellent enantioselectivities (up to 97 % ee).
- Tian, Qinqin,Liu, Yulong,Wang, Xiaoyun,Wang, Xie,He, Wei
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supporting information
p. 3850 - 3855
(2019/06/08)
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- Synthesis and discovery of 18β-glycyrrhetinic acid derivatives inhibiting cancer stem cell properties in ovarian cancer cells
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Despite advances in ovarian cancer treatment, the five-year overall survival rate is less than 30% with the presence of cancer stem cells (CSCs). To develop CSC-targeting therapy, a series of 18β-glycyrrhetinic acid (GA) derivatives containing cinnamamide moiety have been designed, synthesized, and screened for their antiproliferative activity in SKOV3 and OVCAR3 cells. Most of the compounds exhibited stronger antiproliferative activity than GA, and compound 7c was the most active one. Further biological studies showed that compound 7c could induce apoptosis and suppress migration. In addition, compound 7c could not only observably decrease the colony formation and sphere formation ability, but also significantly reduce the CD44+, CD133+, and ALDH+ subpopulation in SKOV3 and OVCAR3 cells. In conclusion, these results indicate that compound 7c is a promising anti-CSC agent for further anti-ovarian cancer studies.
- Li, Xiaojing,Liu, Yihua,Wang, Na,Liu, Yuyu,Wang, Shuai,Wang, Hongmin,Li, Aihua,Ren, Shaoda
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p. 27294 - 27304
(2019/09/12)
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- Design, synthesis and pharmacological evaluation of N4,N6-disubstituted pyrimidine-4,6-diamine derivatives as potent EGFR inhibitors in non-small cell lung cancer
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[Figure presented]A novel series of 4, 6-disubstituted pyrimidines derivatives were designed, synthesized, and evaluated as epidermal growth factor receptor (EGFR) inhibitors for non-small cell lung cancer(NSCLC). 4, 6-disubstituted pyrimidines as core structure was utilized to substitute the lead structure AZD3759 of the quinazoline basic skeleton via an approach involving scaffold hopping. It was found that compound Yfq07 exhibited the best inhibitory effect compared with AZD3759 in vitro and in vivo: Yfq07 exhibited a competitive ATP inhibitory effect, multiple target effects, and further featured a stronger activity against H3255, A431, HCC827, PC-9 and H1975 compared to AZD3759. Moreover, a stronger pro-apoptotic effect, inhibition of cell G2/M phase on A431, H3255, HCC827 and H1975 could also be observed. In this study, the ultimate goal was changing the core structure to improve other epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) properties while retaining the overall potency. Yfq07 was further explored as an effective 4, 6-pyrimidine anticancer agent for the treatment of human NSCLC.
- Zhang, Yuan,Lv, Handeng,Luo, Lu,Xu, Yong,Pan, Yaqian,Wang, Yuewu,Lin, Han,Xiong, Jianhua,Guo, Ping,Zhang, Jinsan,Li, Xiaokun,Ye, Faqing
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p. 1300 - 1325
(2018/09/13)
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- Stereocontrolled Synthesis of trans/ cis-2,3-Disubstituted Cyclopropane-1,1-diesters and Applications in the Syntheses of Furanolignans
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A new Michael addition/intramolecular alkylation sequence of (Z)-3-(2-bromo-3-arylacryloyl)oxazolidin-2-ones and malonates was developed. By a simple switch of the reaction conditions including the base promoter, solvent, and reaction temperature, both of the cis- and trans-isomers of a series of oxazolidinone-containing 2,3-disubstituted cyclopropane-1,1-diesters could be obtained in good-to-excellent yields and with an excellent diastereoselectivity. The utility of the cyclopropane products was demonstrated in the diastereoselective syntheses of (±)-urinaligran and a stereoisomer of (±)-virgatusin involving the AlCl3-promoted [3+2] annulation with veraldehyde or piperonal as the key step.
- Shen, Yue,Chai, Jun,Yang, Gaosheng,Chen, Wenlong,Chai, Zhuo
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supporting information
p. 12549 - 12558
(2018/10/09)
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- Development of sulfonamides incorporating phenylacrylamido functionalities as carbonic anhydrase isoforms I, II, IX and XII inhibitors
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A series of novel sulfonamides incorporating phenylacrylamido functionalities were synthesized and investigated for the inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The physiologically and pharmacologically relevant human (h) isoforms hCA I and II (cytosolic isozymes), as well as the transmembrane tumor-associated hCA IX and XII were included in the study. These compounds showed low nanomolar or sub-nanomolar inhibition constants against hCA II (KIs in the range of 0.50–50.5 nM), hCA IX (KIs of 1.8–228.5 nM), and hCA XII (KIs of 3.5–96.2 nM) being less effective as inhibitors of the off target isoform hCA I. A detailed structure–activity relationship study demonstrates that the nature and position of substituents present on the aromatic part of the scaffold strongly influence the inhibition of CA isoforms. As hCA II, IX and XII are involved in pathologies such as glaucoma and hypoxic, and metastatic tumors, compounds of the type reported in this work may be useful preclinical candidates.
- Angapelly, Srinivas,Ramya, P.V. Sri,Angeli, Andrea,Del Prete, Sonia,Capasso, Clemente,Arifuddin, Mohammed,Supuran, Claudiu T.
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p. 5726 - 5732
(2017/10/09)
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- Novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives as topoisomerase I inhibitors
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In this study, two series of novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives containing an α,β-unsaturated lactone fragment were synthesized and screened for Topo I inhibition and antitumor activity. The topoisomerase I inhibitory activities and cytotoxicities against three human cancer cell lines (MCF-7,Hela,A549) were evaluated. The results revealed that series 2, compounds bearing an exocyclic double bond on the furanone ring, generally showed more potent activity than series 1, compounds lacking an exocyclic double bond. Several compounds of series 2 possess significant Topo I inhibitory activity and potent antiproliferative activity against cancer cell lines. Further mechanism studies of the most active compound of series 2 (B-15) indicated that synthetic compounds can not only stabilize the drug-enzyme-DNA covalent ternary complex as well as camptothecin, but also interfere with the binding between Topo I and DNA. The binding patterns of these compounds with Topo I and structure-activity relationships are discussed.
- Peng, Cheng-Kang,Zeng, Ting,Xu, Xing-Jun,Chang, Yi-Qun,Hou, Wen,Lu, Kuo,Lin, Hui,Sun, Ping-Hua,Lin, Jing,Chen, Wei-Min
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p. 187 - 199
(2017/01/06)
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- Synthesis and in?vitro and in?vivo antitumour activity study of 11-hydroxyl esterified bergenin/cinnamic acid hybrids
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Fourteen bergenin/cinnamic acid hybrids were synthesized, characterized and evaluated for their antitumour activity both in?vitro and in?vivo. The most potent compound, 5c, arrested HepG2 cells (IC50?=?4.23?±?0.79?μM) in the G2/M phase and induced cellular apoptosis. Moreover, compound 5c was also found to suppress the tumour growth in Heps xenograft-bearing mice with low toxicity. In the mechanistic study, 5c administration ignited a mitochondria-mediated apoptosis pathway of HepG2 cell death. Furthermore, 5c activated Akt-dependent pathways and further decreased the expression of the Bcl-2 family of proteins. The downstream mitochondrial p53 translocation was also significantly activated, accompanied by an increase of the caspase-9, caspase-3 activation. These data imply that bergenin/cinnamic acid hybrids could serve as novel Akt/Bcl-2 inhibitors for further preclinical studies.
- Liang, Chengyuan,Pei, Shaomeng,Ju, Weihui,Jia, Minyi,Tian, Danni,Tang, Yonghong,Mao, Gennian
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p. 319 - 328
(2017/04/11)
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- Photochemical Synthesis of 3-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery
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We have developed a rapid two-step synthesis of substituted 3-azabicyclo[3.2.0]heptanes which are attractive building blocks for drug discovery. This new method utilizes very common chemicals, benzaldehyde, allylamine, and cinnamic acid, via intramolectul
- Denisenko, Aleksandr V.,Druzhenko, Tetiana,Skalenko, Yevhen,Samoilenko, Maryna,Grygorenko, Oleksandr O.,Zozulya, Sergey,Mykhailiuk, Pavel K.
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p. 9627 - 9636
(2017/09/23)
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- Copper-catalyzed highly selective synthesis of 2-benzyl- and 2-benzylidene-substituted benzo[: B] thiazinones from 2-iodophenylcinnamamides and potassium sulfide
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An efficient and practical procedure for the synthesis of 2-benzyl- and 2-benzylidene-substituted benzo[b]thiazinones from easily available 2-iodophenylcinnamamides and potassium sulfide has been developed. In the presence of DBU, the reaction proceeds vi
- Liu, Wenjuan,Min, Hao,Zhu, Xiaoming,Deng, Guobo,Liang, Yun
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supporting information
p. 9804 - 9808
(2017/12/08)
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- Lithocholic acid-3-oxime ester compound, and preparation method and application thereof
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The invention discloses a lithocholic acid-3-oxime ester compound shown in a formula (I), and a preparation method thereof. The preparation method comprises the following steps: reacting substituted cinnamic acid and sulfoxide chloride to obtain substitut
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Paragraph 0039
(2017/12/27)
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- A novel serine racemase inhibitor suppresses neuronal over-activation in vivo
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Serine racemase (SRR) is an enzyme that produces D-serine from L-serine. D-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and Aβ peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs’ over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states. In the previous study, we performed in silico screening to identify four compounds with inhibitory activities against recombinant SRR. Here, we synthesized 21 derivatives of candidate 1, one of four hit compounds, and performed screening by in vitro evaluations. The derivative 13J showed a significantly lower IC50 value in vitro, and suppressed neuronal over-activation in vivo.
- Mori, Hisashi,Wada, Ryogo,Takahara, Satoyuki,Horino, Yoshikazu,Izumi, Hironori,Ishimoto, Tetsuya,Yoshida, Tomoyuki,Mizuguchi, Mineyuki,Obita, Takayuki,Gouda, Hiroaki,Hirono, Shuichi,Toyooka, Naoki
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p. 3736 - 3745
(2017/06/13)
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- Bioactivity and structure-activity relationship of cinnamic acid esters and their derivatives as potential antifungal agents for plant protection
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A series of cinnamic acid esters and their derivatives were synthesized and evaluated for antifungal activities in vitro against four plant pathogenic fungi by using the mycelium growth rate method. Structure-activity relationship was derived also. Almost all of the compounds showed some inhibition activity on each of the fungi at 0.5 mM. Eight compounds showed the higher average activity with average EC50 values of 17.4-28.6 μg/mL for the fungi than kresoxim-methyl, a commercial fungicide standard, and ten compounds were much more active than commercial fungicide standards carbendazim against P. grisea or kresoxim-methyl against both P. grisea and Valsa Mali. Compounds C1 and C2 showed the higher activity with average EC50 values of 17.4 and 18.5 μg/mL and great potential for development of new plant antifungal agents. The structure-activity relationship analysis showed that both the substitution pattern of the phenyl ring and the alkyl group in the alcohol moiety significantly influences the activity. There exists complexly comprehensive effect between the substituents on the phenyl ring and the alkyl group in the alcohol moiety on the activity. Thus, cinnamic acid esters showed great potential the development of new antifungal agents for plant protection due to high activity, natural compounds or natural compound framework, simple structure, easy preparation, low-cost and environmentally friendly.
- Zhou, Kun,Chen, Dongdong,Li, Bin,Zhang, Bingyu,Miao, Fang,Zhou, Le
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- Preparation method and product of carbazolyl-containing chalcone
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The invention discloses a preparation method of carbazole-containing chalcone. The preparation method comprises the following steps: a formulated amount of substituted acrylic acid (A) and phosphorus pentachloride (B) are added into a reaction vessel, and
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Paragraph 0062
(2018/03/28)
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- Synthesis and biological evaluation of N-cinnamoyl and mandelate metformin analogues
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A series of N,N-dimethyl-N1-[3-(substituted phenyl)-1-oxo-2-propenyl]biguanides were synthesized by coupling a solution of metformin in pyridine with different cinnamoyl chloride derivatives in ether for 3 h in addition to synthesis of some five molecules of metformin-mandelates. All the synthesized cinnamoyl metformins and a few metformin-mandelates were characterized by IR, NMR and Mass spectroscopic techniques. All the synthesized compounds were also evaluated for their antioxidant activity by DPPH scavenging method and nitric oxide scavenging method. All the compounds exhibited good antioxidant activity.
- Anitha Kumari,Bharathi,Prabhu,Ponnudurai
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p. 1895 - 1898
(2016/07/06)
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- Design, synthesis and antimycobacterial activity of novel imidazo[1,2-a]pyridine amide-cinnamamide hybrids
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We report herein the design and synthesis of a series of novel imidazo[1,2- A]pyridine amide-cinnamamide hybrids linked via an alkyl carbon chain. All 38 new hybrids were evaluated for their antimycobacterial activity against M. tuberculosis (MTB) H37Rv ATCC 27294 using the microplate Alamar Blue assay (MABA). Although the hybrids are less active than the two reference compounds, the promising activity (MICs: 4 μg/mL) of 2,6-dimethylimidazo[1,2-a]pyridine amide-cinnamamide hybrids 11e and 11k could be a good starting point to further find new lead compounds against multi-drug-resistant tuberculosis.
- Li, Linhu,Li, Zhuorong,Liu, Mingliang,Shen, Weiyi,Wang, Bin,Guo, Huiyuan,Lu, Yu
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- Synthesis and biological evaluation of arylcinnamide linked combretastatin-A4 hybrids as tubulin polymerization inhibitors and apoptosis inducing agents
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A series of new molecules have been designed based on a hybridization approach by combining the arylcinnamide and combretastatin pharmacophores. These were synthesized and evaluated for their cytotoxic activity, effect on inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant cytotoxic activity against some representative human cancer cell lines and two of the conjugates 6i and 6p displayed potent cytotoxicity with GI50 values of 56 nM and 31 nM respectively against the human breast cancer cell line (MCF-7). SAR studies revealed that 3,4-substitution on the phenyl ring of the cinnamide moiety is beneficial for enhanced cytotoxicity. Moreover, G2/M cell cycle arrest was induced by these conjugates (6i and 6p) apart from tubulin polymerization inhibition (IC50 of 1.97 μM and 1.05 μM respectively). Further, mitochondrial membrane potential, Annexin V-FITC and caspase-9 activation assays suggested that these conjugates induce cell death by apoptosis. Docking studies revealed that these conjugates interact and bind at the colchicine binding site of the tubulin.
- Kamal, Ahmed,Bajee, Shaik,Lakshma Nayak, Vadithe,Venkata Subba Rao, Ayinampudi,Nagaraju, Burri,Ratna Reddy, Challa,Jeevak Sopanrao, Kapure,Alarifi, Abdullah
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supporting information
p. 2957 - 2964
(2016/06/06)
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- Conjugate addition of aryl nucleophiles to α,β-unsaturated cinnamic acid derivatives containing Evans type chiral auxiliaries
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Cinnamides containing oxazolidin-2-one type auxiliaries have been prepared. A novel pathway to chiral 4-aryl-6-methyl-3,4-dihydrocoumrines via the asymmetric conjugate addition of arylmagnesium bromides to these cinnamides is described.
- Leitis, Zigmārs,Lūsis, Viesturs
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p. 843 - 851
(2016/09/02)
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- Design, synthesis and cytotoxic evaluation of novel imatinib amide derivatives that target Abl kinase
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Novel imatinib amide derivatives (a1-28, b1-9) were synthesized and evaluated for their biological activities. All compounds were characterized by 1H NMR, MS and elemental analysis. Among all the derivatives, compounds a4, a10, a21, b1 and b2 displayed the most significant ability of inhibiting K562 cell proliferation with the IC50 values of 0.67, 0.66, 0.65, 0.59 and 0.62 μM, respectively, indicating that these compounds were potent inhibitors of Bcr-Abl in leukemic K562 cells, comparable to the reference compound imatinib. Molecular docking study was performed to position compounds a21 and b1 into the active site of Abl to determine the probable binding modes
- Yao, Ri-Sheng,Guan, Qiu-Xiang,Lu, Xiao-Qin,Ruan, Ban-Feng
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- Design, synthesis and antibacterial activity of cinnamaldehyde derivatives as inhibitors of the bacterial cell division protein FtsZ
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In an attempt to discover potential antibacterial agents against the increasing bacterial resistance, novel cinnamaldehyde derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activity against nine significant pathogens using broth microdilution method, and their cell division inhibitory activity against four representative strains. In the in vitro antibacterial activity, the newly synthesized compounds generally displayed better efficacy against Staphylococcus aureus ATCC25923 than the others. In particular, compounds 3, 8 and 10 exerted superior or comparable activity to all the reference drugs. In the cell division inhibitory activity, all the compounds showed the same trend as their in vitro antibacterial activity, exhibiting better activity against S. aureus ATCC25923 than the other strains. Additionally, compounds 3, 6, 7 and 8 displayed potent cell division inhibitory activity with an MIC value of below 1 1/4g/mL, over 256-fold better than all the reference drugs.
- Li, Xin,Sheng, Juzheng,Huang, Guihua,Ma, Ruixin,Yin, Fengxin,Song, Di,Zhao, Can,Ma, Shutao
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- Synthesis and antibacterial activity of 4'3-O-(trans-β-arylacrylamido)carbamoyl azithromycin analogs
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Novel 4'3-O-(trans-β-arylacrylamido)carbamoyl azithromycin analogs were designed, synthesized and evaluated for their antibacterial activity against nine significant pathogens using broth microdilution method. A majority of these derivatives maintained the activity of azithromycin against susceptible Streptococcus pyogenes and all the compounds demonstrated remarkably improved activity compared with the references against all the three phenotypes of resistant Streptococcus pneumoniae. In particular, compound 24 exhibited the most potent activity against susceptible Staphylococcus aureus (MIC = 0.5 μg/mL), S. pneumoniae (MIC = 0.06 μg/mL) and S. pyogenes (MIC = 0.25 μg/mL). The most active compound 7 (MIC = 0.015 μg/mL) against resistant S. pneumoniae expressing the mefA gene, exhibited 512 and 256-fold more potent activity than erythromycin and azithromycin, respectively. Compounds 28 (MIC = 0.5 μg/mL), 29 (MIC = 0.25 μg/mL) and 30 (MIC = 0.5 μg/mL) demonstrated potent activity against resistant S. pneumoniae expressing the ermB gene, which were 256, 512 and 256-fold better than the references, respectively.
- Yan, Mi,Ma, Xiaodong,Dong, Ruiqian,Li, Xin,Zhao, Can,Guo, Zhenzhen,Shen, Yan,Liu, Fang,Ma, Ruixin,Ma, Shutao
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p. 506 - 515
(2015/10/06)
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- Synthesis, in vitro and in vivo antitumor activity of scopoletin-cinnamic acid hybrids
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A series of hybrids of scopoletin and substituted cinnamic acid were designed, synthesized and evaluated in vitro and in vivo against five human tumor cell lines [MCF-7, MDA-MB-231, A549, HCT-116, and HeLa] with doxorubicin as the positive control. Compounds 17a, 17b, 17c and 17g exhibited potent cytotoxic activity. Especially, compound 17b displayed broad spectrum activity with IC50 values ranging from 0.249 μ1/4M to 0.684 μ1/4M. Moreover, in a preliminary pharmacological study, 17b not only remarkably induced cellular apoptosis, but also clearly induced A549 cells cycle arrest at S phase. In vivo study showed that 17b significantly suppressed tumor growth in a dose-dependent manner without causing the loss of the mean body weight of mice, which was superior to doxorubicin. These preliminary results indicate that 17b is an optimal anti-cancer leading compound and merit further structural modification.
- Li, Linhu,Zhao, Peng,Hu, Jinglin,Liu, Jinhong,Liu, Yan,Wang, Zhiqiang,Xia, Yufeng,Dai, Yue,Chen, Li
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p. 300 - 307
(2015/03/04)
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- Fluoro-substituted phenylazocarboxamides: Dopaminergic behavior and N-arylating properties for irreversible binding
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Phenylazocarboxamides can serve as bioisosteres for cinnamides, which are widely occurring substructures in medicinal chemistry. Starting from our lead compound 2, the introduction of additional fluoro substituents and the exchange of the methoxyphenylpip
- Bartuschat, Amelie L.,Schellhorn, Tamara,Hübner, Harald,Gmeiner, Peter,Heinrich, Markus R.
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p. 3938 - 3947
(2015/06/22)
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- Base-promoted new C-C bond formation: An expedient route for the preparation of thiazolo- and imidazolo-pyridinones via Michael addition
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Base-catalyzed one-pot cyclocondensation reactions of acryloyl and cinnamoyl chlorides with β-nitroenamine derivatives have been performed under mild conditions and target 7-substituted thiazolo-[3,2-a] or imidazolo-[1,2-a]pyridin-5-one derivatives were prepared successfully in moderate to good yields. The cyclization reactions may proceed via Michael addition followed by iminoketene-amide tautomerization in view of the products formed.
- Yildirim, Muhammet,C?elikel, Derya,Evis, Naciye,Knight, David W.,Kariuki, Benson M.
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p. 5674 - 5681
(2015/03/30)
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- Multifunctional novel Diallyl disulfide (DADS) derivatives with β-amyloid-reducing, cholinergic, antioxidant and metal chelating properties for the treatment of Alzheimer's disease
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A series of novel Diallyl disulfide (DADS) derivatives were designed, synthesized and evaluated as chemical agents, which target and modulate multiple facets of Alzheimer's disease (AD). The results showed that the target compounds 5a-l and 7e-m exhibited significant anti-Aβ aggregation activity, considerable acetylcholinesterase (AChE) inhibition, high selectivity towards AChE over butyrylcholinesterase (BuChE), potential antioxidant and metal chelating activities. Specifically, compounds 7k and 7l exhibited highest potency towards self-induced Aβ aggregation (74% and 71.4%, 25 μM) and metal chelating ability. Furthermore, compounds 7k and 7l disaggregated Aβ fibrils generated by Cu2+-induced Aβ aggregation by 80.9% and 78.5%, later confirmed by transmission electron microscope (TEM) analysis. Besides, 7k and 7l had the strongest AChE inhibitory activity with IC50 values of 0.056 μM and 0.121 μM, respectively. Furthermore, molecular modelling studies showed that these compounds were capable of binding simultaneously to catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. All the target compounds displayed moderate to excellent antioxidant activity with ORAC-FL values in the range 0.546-5.86 Trolox equivalents. In addition, absorption, distribution, metabolism and excretion (ADME) profile and toxicity prediction (TOPKAT) of best compounds 7k and 7l revealed that they have drug like properties and possess very low toxic effects. Collectively, the results strongly support our assertion that these compounds could provide good templates for developing new multifunctional agents for AD treatment.
- Manral, Apra,Saini, Vikas,Meena, Poonam,Tiwari, Manisha
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p. 6389 - 6403
(2015/10/05)
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- UV light-mediated difunctionalization of alkenes through aroyl radical addition/1,4-/1,2-Aryl shift cascade reactions
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UV light-mediated difunctionalization of alkenes through an aroyl radical addition/1,4-/1,2-aryl shift has been described. The resulted aroyl radical from a photocleavage reaction added to acrylamide compounds followed by cyclization led to the formation of oxindoles, whereas the addition to cinnamic amides aroused a unique 1,4-aryl shift reaction. Furthermore, the difunctionalization of alkenes of prop-2-en-1-ols was also achieved through aroyl radical addition and a sequential 1,2-aryl shift cascade reaction.
- Zheng, Lewei,Huang, Hongli,Yang, Chao,Xia, Wujiong
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supporting information
p. 1034 - 1037
(2015/03/30)
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- A novel direct synthesis of 3-acyl-4-aryldihydroquinolin-2(1H)-ones via metal-free radical tandem cyclization between N-arylcinnamamides and aldehydes
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An efficient metal-free and practical method for the synthesis of disubstituted dihydroquinolin-2(1H)-ones via intermolecular radical tandem addition/cyclization was developed. This method provides a novel and straightforward route to 3-acyl-4-aryldihydro
- Mai, Wen-Peng,Wang, Ji-Tao,Xiao, Yong-Mei,Mao, Pu,Lu, Kui
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p. 8041 - 8051
(2015/12/31)
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- Synthesis and biological evaluation of cinnamido linked benzophenone hybrids as tubulin polymerization inhibitors and apoptosis inducing agents
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A new class of hybrid molecules containing cinnamide subunit linked to benzophenone as inhibitors of tubulin polymerization were synthesized and evaluated for their anticancer potential. These hybrids exhibit anticancer activity with IC50 values ranging from 0.06 to 16.3 μM. Compounds 4f and 4g possessing fluoro and trifluoromethyl on the cinnamido subunit showed significant cytotoxic activity with IC50 values 0.06 and 0.09 μM against HeLa cell line, respectively. These compounds showed cell cycle arrest at G2/M phase of the cell cycle and inhibited tubulin polymerization followed by activation of caspase-3 activity and apoptotic cell death. Further in vitro tubulin polymerization assay showed that the level of tubulin inhibition was comparable to that of 2a for the compounds 4f and 4g. Moreover, Hoechst 33258 staining and DNA fragmentation assay suggested that these compounds induce cell death by apoptosis. Overall, the current study demonstrates that the synthesis of benzophenone linked cinnamide subunit conjugates as promising anticancer agents with G2/M arrest and apoptotic-inducing ability via targeting tubulin.
- Kamal, Ahmed,Reddy, Ch. Ratna,Vishnuvardhan,Mahesh,Lakshma Nayak,Prabhakar,Reddy, C. Suresh
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supporting information
p. 2309 - 2314
(2014/05/20)
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