Browsing by Author "Sun, Chung-Ming"

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5-phenylpyridazinones - A serendipitous route from coumarins
(2008-07-07)
Ghate, Manjunath D.
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Jadhav, Vithal B.
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Shastri, Lokesh A.
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Kulkarni, Manohar V.
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Kulkarni, Geetha M.
A new route of the ring transformation has been discovered during the reaction of 4-bromomethylcoumarins with hydrazine hydrate leading to the formation of pharmacologically important pyridazinones in a single step with very high yields. These so obtained pyridazinones have the potential for further functional group interconversions. (C) 2008 Elsevier Ltd. All rights reserved.
A concise synthesis of 2-(2-aminothiophene)-benzimidazoles by one-pot multicomponent reaction
(2013)
Chen, Li-Hsun
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Chuang, Ying-Sheng
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Narhe, Bharat D.
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Sun, Chung-Ming
;
應用化學系
A one-pot synthesis of 2-aminothiophene linked benzimidazoles was achieved by utilizing 2-cyanomethyl benzimidazoles in a modified Gewald multicomponent reaction. The synthetic strategy of the reaction involved treatment of 2-(cyanomethyl)-benzimdazole with aldehydes containing an active methylene group and sulfur powder under refluxing conditions. The multicomponent reaction proceeded via Knoevenagel condensation of 2-(cyanomethyl)-benzimdazole with aldehyde to generate an alpha,beta-unsaturated nitrile followed by cyclization with molecular sulfur under basic conditions to give biologically relevant 2-(2-aminothiophene)-benzimidazoles in good yields.
A highly selective fluorescent chemosensor for Ag+ based on calix[4]arene with lower-rim proximal triazolylpyrenes
(2012-08-01)
Wang, Nae-Jen
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Sun, Chung-Ming
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Chung, Wen-Sheng
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應用化學系
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Department of Applied Chemistry
Ligand 3, a calix[4]arene with lower-rim proximal triazolylpyrenes, is a ratiometric fluorescent chemosensor for Ag+ with higher sensitivity compared to ligand 5, a calix[4]arene with lower-rim distal triazolylpyrenes, and the conventional fluoroionophore with non-conjugated triazole and pyrene. In a polar protic solvent, the binding ratios for 3 center dot Ag+ was determined to be 1:1 and the association constant was found to be 7.0 x 10(3) M-1. The detection of Ag+ by ligand 3 even works in aqueous methanol solution. (C) 2012 Elsevier B.V. All rights reserved.
A Novel Mechanistic Study on Ultrasound-Assisted, One-Pot Synthesis of Functionalized Benzimidazo[2,1-b]quinazolin-1(1H)-ones
(2016-03)
Chen, Li-Hsun
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Chung, Tsai-Wen
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Narhe, Bharat D.
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Sun, Chung-Ming
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應用化學系
Ultrasound-assisted synthesis of benzimidazo[2,1-b]quinazolin-1(1H)-ones was achieved via piperidine-catalyzed three-component reaction of 2-aminobenzimidazoles, an aromatic aldehyde, and 1,3-dione in aqueous isopropanol. This mechanism was first suspected following our identification of unusual reaction intermediates in a one-pot reaction. An unprecedented coupling reaction, it involved a nucleophilic attack by 2-aminobenzimidazole on in situ generated Michael adduct, followed by electrocyclic ring formation reaction. In contrast to the commonly accepted mechanism, that the direct reaction of 2-amino benzimidazole with a Knoevenagel adduct cannot deliver target compounds.
A proteomic approach to study molecular mechanisms of andrographolide-mediated degradation of Src oncoproteins.
(2013-04-15)
Liu, Sheng-Hung
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Chen, Pei-Fen
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Lin, Chao-Hsiung
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Sun, Chung-Ming
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Chi, Chin-Wen
A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors
(2020-06-29)
Hsu, Kai-Cheng
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HuangFu, Wei-Chun
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Lin, Tony Eight
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Chao, Min-Wu
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Sung, Tzu-Ying
The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC50 value of 2.7, 4.2, and 5.3 mu M, respectively. All three inhibitors significantly decrease LPS-induced TNF-alpha and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs.
A specific and ratiometric chemosensor for Hg(2+) based on triazole coupled ortho-methoxyphenylazocalix[4]arene
(2011-10-21)
Wang, Nae-Jen
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Sun, Chung-Ming
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Chung, Wen-Sheng
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應用化學系
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Department of Applied Chemistry
Calix[4]arene 3, which contains two distal triazole groups on the lower rim and two distal o-methoxyphenylazo groups on the upper rim, was synthesized and found to be a specific and ratiometric sensor for Hg(2+) in a polar protic solvent. A series of o-methoxyphenylazo derivatives (3, 4, 5, 7, and 9) were synthesized, which proved that the lower-rim triazoles and the hydroxyl azophenol(s) were the major ligands for metal ion binding. Though analogues 4 and 10 showed some sensitivity for Hg(2+), compound 3 was the only ratiometric chemosensor for Hg(2+) among the series of azocalix[4]arenes synthesized in this work. The formation of 3. Hg(2+) complex was supported by UV/vis and NMR titration studies and Mass spectrometry. Based on the symmetrical features of NMR spectra of 3 center dot Hg(2+), the complex is believed to be symmetrical with respect to the calix[4]arene cavity. Furthermore, the complex was determined to be 1:1 binding stoichiometry by Job's plot, and the association constant was determined to be 4.02 x 10(3) M(-1) using Benesi-Hildebrand plot. (C) 2011 Elsevier Ltd. All rights reserved.
A specific and ratiometric chemosensor for Hg2+ based on triazole coupled ortho-methoxyphenylazocalix[4]arene
(2011-10-21)
Wang, Nae-Jen
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Sun, Chung-Ming
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Chung, Wen-Sheng
;
應用化學系
;
Department of Applied Chemistry
Calix[4]arene 3, which contains two distal triazole groups on the lower rim and two distal o-methoxyphenylazo groups on the upper rim, was synthesized and found to be a specific and ratiometric sensor for Hg2+ in a polar protic solvent. A series of o-methoxyphenylazo derivatives (3, 4, 5, 7, and 9) were synthesized, which proved that the lower-rim triazoles and the hydroxyl azophenol(s) were the major ligands for metal ion binding. Though analogues 4 and 10 showed some sensitivity for Hg2+, compound 3 was the only ratiometric chemosensor for Hg2+ among the series of azocalix[4]arenes synthesized in this work. The formation of 3. Hg2+ complex was supported by UV/vis and NMR titration studies and Mass spectrometry. Based on the symmetrical features of NMR spectra of 3 center dot Hg2+, the complex is believed to be symmetrical with respect to the calix[4]arene cavity. Furthermore, the complex was determined to be 1:1 binding stoichiometry by Job's plot, and the association constant was determined to be 4.02 x 10(3) M-1 using Benesi-Hildebrand plot. (C) 2011 Elsevier Ltd. All rights reserved.
A Telescoping Synthesis of Chimeric Polyheterocycles through a Piperidine-Mediated Multicomponent Reaction
(2013-04-01)
Lee, Chia-Hsin
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Hsu, Wei-Shun
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Chen, Chih-Hau
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Sun, Chung-Ming
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應用化學系
A new piperidine-catalyzed Groebke-Bienayme-Blackburn (GBB) multicomponent reaction of 2-aminobenzimidazoles, methyl 2-formylbenzoate, and isocyanides has been explored. A facile and straightforward postmodification leads to isoquinolinone-embedded imidazo[1,2-a]benzimidazoles. Insight into a plausible mechanism is discussed and supported by X-ray crystal structure analysis.
Anchor-based classification and type-C inhibitors for tyrosine kinases
(2015-06-16)
Hsu, Kai-Cheng
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Sung, Tzu-Ying
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Lin, Chih-Ta
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Chiu, Yi-Yuan
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Hsu, John T. -A.
Tyrosine kinases regulate various biological processes and are drug targets for cancers. At present, the design of selective and anti-resistant inhibitors of kinases is an emergent task. Here, we inferred specific site-moiety maps containing two specific anchors to uncover a new binding pocket in the C-terminal hinge region by docking 4,680 kinase inhibitors into 51 protein kinases, and this finding provides an opportunity for the development of kinase inhibitors with high selectivity and anti-drug resistance. We present an anchor-based classification for tyrosine kinases and discover two type-C inhibitors, namely rosmarinic acid (RA) and EGCG, which occupy two and one specific anchors, respectively, by screening 118,759 natural compounds. Our profiling reveals that RA and EGCG selectively inhibit 3% (EGFR and SYK) and 14% of 64 kinases, respectively. According to the guide of our anchor model, we synthesized three RA derivatives with better potency. These type-C inhibitors are able to maintain activities for drug-resistant EGFR and decrease the invasion ability of breast cancer cells. Our results show that the type-C inhibitors occupying a new pocket are promising for cancer treatments due to their kinase selectivity and anti-drug resistance.
Andrographolide and its potent derivative exhibit anticancer effects against imatinib-resistant chronic myeloid leukemia cells by downregulating the Bcr-Abl oncoprotein
(2019-05-01)
Liao, Hsin-Chia
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Chou, Yi-Ju
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Lin, Ching-Cheng
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Liu, Sheng-Hung
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Oswita, Audrey
Chronic myelogenous leukemia (CML) is clinically treated with imatinib, which inhibits the kinase activity of the Bcr-Abl oncoprotein. However, imatinib resistance remains a common clinical issue. Andrographolide, the major compound of the medicinal plant Andrographis paniculata, was reported to exhibit anticancer activity. In this study, we explored the therapeutic potential of andrographolide and its derivative, NCTU-322, against both imatinib-sensitive and imatinib-resistant human CML cell lines. Both andrographolide and NCTU-322 down regulated the Bcr-Abl oncoprotein in imatinib-resistant CML cells through an Hsp90-dependent mechanism similar to that observed in imatinib-sensitive CML cells. In addition, NCTU-322 had stronger effects than andrographolide on downregulation of Bcr-Abl oncoprotein, induction of Hsp90 cleavage and cytotoxicity of CML cells. Notably, andrographolide and NCTU-322 could induce differentiation, mitotic arrest and apoptosis of both imatinib-sensitive and imatinib-resistant CML cells. Finally, the anticancer activity of NCTU-322 against imatinib-resistant CML cells was demonstrated in vivo. In summary, our data demonstrated that andrographolide and NCTU-322 inhibit Bcr-abl function via a mechanism different from that of imatinib, and they induced multiple anticancer effects in both imatinib-sensitive and resistant CML cells. Our findings demonstrate that andrographolide and NCTU-322 are potential therapeutic agents again CML.
Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy
(2014-01-15)
Liu, Sheng-Hung
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Lin, Chao-Hsiung
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Liang, Fong-Ping
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Chen, Pei-Fen
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Kuo, Cheng-Deng
Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90 alpha was identified in andrographolide-treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity. (C) 2013 Elsevier Inc. All rights reserved.
Base Controlled Three-Component Regioselective Synthesis of 2-Imino Thiazolines and 2-Thioxoimidazolin-4-ones
(2019-04-01)
Barve, Indrajeet J.
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Chang, Wong-Jin
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Lin, Yen-Tzu
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Thikekar, Tushar Ulhas
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Sun, Chung-Ming
Base-controlled regioselective synthesis of 2-imino thiazolines and 2-thioxoimidazolin-4-ones was achieved to use a one-pot reaction between chiral amino esters, isothiocyanates, and alpha-bromoketones/alkyl halides. This three-component coupling reaction in acetonitrile provides 2-imino thiazolines, whereas the formation of 2-thioxoimidazolin-4-ones was observed under basic conditions at ambient temperature. The corresponding products were obtained in good to excellent yield with broad substrate scope. Isolation of thiourea and thiohydantoin intermediates disclosed the course of the reaction mechanism.
Base-Catalyzed Povarov Reaction: An Unusual [1,3] Sigmatropic Rearrangement to Dihydropyrimidobenzimidazoles
(2011-10-07)
Chen, Chih-Hau
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Yellol, Gorakh S.
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Lin, Po-Tsung
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Sun, Chung-Ming
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應用化學系
A novel base-catalyzed Povarov reaction of arylamines, aldehydes, and electron-deficient dienophiles has been developed. An unprecedented in situ [1,3] sigmatropic rearrangement leading to 4,10-dihydropyrimido[1,2-a]benzimidazoles has also been discovered. An insight of the plausible mechanism is discussed and supported by X-ray crystal study. This cascade reaction is achieved in a one-pot multicomponent fashion on soluble support under microwave conditions.
Bicyclic Heteroaryl Compounds
(2011-04-07)
Sun, Chung-Ming
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Kuo, Min-Liang
Bicyclic heteroaryl compounds of formula (I) shown below are disclosed. Each variable in formula (I) is defined in the specification. Also disclosed is treatment of cancer with these compounds.
Cascade Synthesis of Benzimidazole-Linked Pyrroles via Copper Catalyzed Oxidative Cyclization and Ketonization
(2017-06-16)
Ye, Tzuen-Yang
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Selvaraju, Manikandan
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Sun, Chung-Ming
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應用化學系
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Department of Applied Chemistry
A three-component cascade reaction of 2-aminobenzimidazole, aldehyde, and terminal alkyne has been explored for an efficient synthesis, of benzimidazole-linked tetrasubstituted pyrroles. The reaction sequence involves the formation Of propargylamine, insertion of 4 terminal alkyne, and a ring opening reaction, followed by, an intramolecular carboylative cyclization under aerobic conditions. It represents a novel, strategy to the construction of C=N, C=C, C=0 bonds and a new five-membered 2-ketopyrrole ring. In this process, the reaction conditions are crucial and an attempt to elucidate the novel reaction patway is well, supported by X=ray crystallography.
Catalyst-Controlled Chemodivergent Annulation to Indolo/Pyrrolo-Fused Diazepine and Quinoxaline
(2019-06-18)
Dhole, Sandip
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Chiu, Wei-Jung
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Sun, Chung-Ming
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應用化學系
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Department of Applied Chemistry
Catalyst-controlled chemodivergent annulation between o-indolo anilines and diazo compounds has explored for the synthesis of indolo-fused diazepine and quinoxaline Under the Rh(III) catalyst, reaction proceeded through the free amine assisted C2-H activation followed by amidation leading to the diazepino [1,7-alpha]indole in a highly selective manner. While with Ru(II) catalyst, reaction involves formation Ru-carbene complex followed by -NH2 group insertion and cascade cyclization via metallo-ene type reaction, beta-hydride elimination to furnish the indolo[1,2-alpha]quinoxaline as the predominating product. This strategy directs modular approach towards the construction of unique indolo-fused diazepine/quinoxaline as well as pyrrolo-fused diazepine/quinoxaline scaffolds in excellent yields.
Catalyst-Controlled Regioselective Synthesis of Benzotriazlolodiazepin-7-ones and Benzotriazolodiazocin-8-ones
(2020-01-17)
Chen, Kai-Chi
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Barve, Indrajeet J.
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Sun, Chung-Ming
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應用化學系
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Department of Applied Chemistry
A catalyst-controlled highly chemoselective and regioselective intramolecular cycloamidation of triazol-1-ylbenzamides toward the synthesis of scarcely known heterocycles is reported. In the presence of a palladium catalyst, this cycloisomerization reaction afforded substituted benzotriazlolodiazepin-7-ones via intramolecular insertion of a palladium into C-C triple bond in a 7-exo-dig way. Alternatively, the use of a silver catalyst in the reaction produced substituted benzotriazolodiazocin-8-ones in a highly regioselective manner through 8-endo-dig intramolecular ring closure.
Convergent Solution Phase Synthesis of Chimeric Oligonucleotides by a 2+2 and 3+3 Phosphoramidite Strategy
(2010)
Chen, Chih-Hau
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Chen, Wei-Yu
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Chen, Yu-Chie
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Lee, Ming-Juan
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Huang, Chyuan-Der
A chimeric oligonucleotide tetramer and hexamer were synthesized by the phosphoramidite approach using a 2+2 and 3+3 strategy, respectively. The concept of convergent synthesis provides an efficient route toward the synthesis of longer chimeric oligonucleotides, such as small interfering RNA oligonucleotides without the pollution of n - 1 or shorter failures. This methodology offers an efficient and economical way to scale-up the synthesis of high purity oligonucleotides for clinical trials and commercial uses.
Copper catalyzed aerobic oxidative cyclization and ketonization: one pot synthesis of benzoimidazo[1,2-a]imidazolones
(2016)
Selvaraju, Manikandan
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Ye, Tzuen-Yang
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Li, Chia-Hsin
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Ho, Pei-Heng
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Sun, Chung-Ming
A highly efficient synthesis of benzoimidazo[1,2-a]imidazolone through a novel oxidative 5-exo-dig cyclization-ketonization cascade of 2-aminobenzimidazole, aldehyde and terminal alkyne has been explored under aerobic conditions. The reaction proceeds through copper-catalyzed addition of terminal alkynes to imines derived from 2-aminobenzimidazole with aldehyde followed by intramolecular cyclization. The atmospheric molecular oxygen acts as an oxygen source for the newly formed carbonyl group in the final product.