Browsing by Author "Chen, Chih-Hau"

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3-8 GHz broadband low power mixer
(2008)
Chen, Chih-Hau
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Jou, Christina F.
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傳播研究所
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Institute of Communication Studies
A 3-8 GHz broadband mixer is presented in this paper. This broadband mixer is low power and high conversion gain. It provides current reuse and ac-coupled folded switching. This mixer is designed in TSMC 0.18-mu m CMOS technology. This broadband mixer achieves simulated conversion gain of 9 +/- 1.5 dB, a single sideband noise figure lower than 15.2 dB and IIP3 batter than -7 dBm. From 3-8 GHz, at supply voltage of 1.5 V power consumption without output buffer is 3.27 mW and power consumption with buffer is about 8 mW. The chip area is 1079 mu m x 761 mu m.
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 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.
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.
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
;
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.
Diastereoselective Synthesis of Bridged Polycyclic Alkaloids via Tandem Acylation/Intramolecular Diels-Alder Reaction
(2013-10-04)
Chen, Chih-Hau
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Yellol, Gorakh S.
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Tsai, Cheng-Hsun
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Dalvi, Prashant B.
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Sun, Chung-Ming
A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-beta-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron beta-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-beta-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key, feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.
Diversity-Oriented Synthesis of Angular Bis-benzimidazole Derivatives under Microwave Irradiation
(2009-11-01)
Chen, Chih-Hau
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Chien, Ming-Hsien
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Kuo, Min-Liang
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Chou, Cheng-Ting
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Lai, Jin-Ji
Pharmaceutically interesting, angular bis-benzimidazoles with three appendages have been synthesized successfully through a diversity-oriented approach with soluble support under microwave irradiation. Polymer immobilized o-phenylenediamine was selectively N-acylated with 2-chloro-3-nitrobenzoic acid in a primary aromatic amino moiety. The obtained amide was cyclized to benzimidazole in an acidic condition, and subsequently nucleophilic aromatic substitution with different amines was performed. Successive reduction, cyclization with various aldehydes and activated isothiocyanates yielded angular biheterocyclic benzimidazoles in good quantities. Reaction progress on polymer support was precisely monitored using the conventional proton NMR spectroscopy. Preliminary screening results showed some of these interesting compounds exhibited moderately to good inhibition against vascular endothelial growth factor receptor 3 (VEGFR-3), which is related to invasion and migration of cancer cells.
Enantioselective Synthesis of Benzimidazolyl Quinoxalinones on Soluble Polymer Support Using Focused Microwave Irradiation
(2009-03-01)
Chanda, Kaushik
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Kuo, Jaren
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Chen, Chih-Hau
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Sun, Chung-Ming
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應用化學系
Focused microwave irradiation has been applied to a multistep synthetic sequence of reactions designed to generate benzimidazolyl quinoxalinones using a soluble polymer support. They were obtained by the ipso-fluoro (S(N)Ar) displacement of the immobilized ortho-nitro fluoro benzimidazoles with chiral alpha amino esters under microwave irradiation. Intermediate chiral organic-polymer conjugates when subjected to neutral reduction underwent a spontaneous intramolecular ring closure. Cleavage of the polymer support, at room temperature, did not cause any significant racemization resulting in the generation of a chiral molecular library with two points of structural diversity.
Exploring a sulfone linker utilizing trimethyl aluminum as a cleavage reagent: solid-phase synthesis of sulfonamides and ureas
(2012-08-01)
Chung, Tsai-Wen
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Chen, Chih-Hau
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Lin, Chu-Chung
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Wu, Hsien-Jen
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Sun, Chung-Ming
A novel and efficient cleavage reagent, trimethyl aluminum, for traceless sulfinate-functionalized resin has been developed. The synthesis of sulfonamide and urea derivatives via a traceless solid-phase sulfone linker strategy through six synthetic steps comprising utilization of trimethyl aluminum as a novel cleavage reagent was also established. An insight of the plausible mechanism of the cleavage reaction was discussed.
Inhibition of Metastatic Potential in Breast Carcinoma In Vivo and In Vitro through Targeting VEGFRs and FGFRs
(2013)
Chien, Ming-Hsien
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Lee, Liang-Ming
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Hsiao, Michael
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Wei, Lin-Hung
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Chen, Chih-Hau
Angiogenesis and lymphangiogenesis are considered to play key roles in tumor metastasis. Targeting receptor tyrosine kinases essentially involved in the angiogenesis and lymphangiogenesis would theoretically prevent cancer metastasis. However, the optimal multikinase inhibitor for metastasis suppression has yet to be developed. In this study, we evaluated the effect of NSTPBP 0100194-A (194-A), a multikinase inhibitor of vascular endothelial growth factor receptors (VEGFRs)/fibroblast growth factor receptors (FGFRs), on lymphangiogenesis and angiogenesis in a mammary fat pad xenograft model of the highly invasive breast cancer cell line 4T1-Luc(+). We investigated the biologic effect of 194-A on various invasive breast cancer cell lines as well as endothelial and lymphatic endothelial cells. Intriguingly, we found that 194-A drastically reduced the formation of lung, liver, and lymph node metastasis of 4T1-Luc(+) and decreased primary tumor growth. This was associated with significant reductions in intratumoral lymphatic vessel length (LVL) and microvessel density (MVD). 194-A blocked VEGFRs mediated signaling on both endothelial and lymphatic endothelial cells. Moreover, 194-A significantly inhibited the invasive capacity induced by VEGF-C or FGF-2 in vitro in both 4T1 and MDA-MB231 cells. In conclusion, these experimental results demonstrate that simultaneous inhibition of VEGFRs/FGFRs kinases may be a promising strategy to prevent breast cancer metastasis.
Microwave-assisted synthesis of highly functionalized guanidines on soluble polymer support
(1970-01-01)
Chen, Chih-Hau
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Tung, Chieh-Li
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Sun, Chung-Ming
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應用化學系
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Department of Applied Chemistry
"An efficient method for the N,N'-di(Boc)-protected guanidines containing piperazine and homopiperazine scaffolds has been developed under multi-step microwave irradiation. Followed by alkylation of carbamate-protected guanidines with various alkyl halides is also explored. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine by sodium hydride on soluble polymer support. In this manner, highly functionalized guanidines were obtained after cleavage from the support. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine components. In addition, the reaction is sufficiently simple workup by precipitation in each step to yield the substituted guanidines in high purity. In conjunction with microwave irradiation and soluble polymer support, this method provides an efficient route to access highly functionalized guanidines. (C) 2012 Elsevier Ltd. All rights reserved."
Multistep divergent synthesis of benzimidazole linked benzoxazole/benzothiazole via copper catalyzed domino annulation
(2013)
Liao, Jen-Yu
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Selvaraju, Manikandan
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Chen, Chih-Hau
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Sun, Chung-Ming
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應用化學系
An efficient, facile synthesis of structurally diverse benzimidazole integrated benzoxazole and benzothiazoles has been developed. In a multi-step synthetic sequence, 4-fluoro-3-nitrobenzoic acid was converted into benzimidazole bis-heterocycles, via the intermediacy of benzimidazole linked ortho-chloro amines. The amphiphilic reactivity of this intermediate was designed to achieve the title compounds by the reaction of various acid chlorides and isothiocyanates in a single step through the in situ formation of ortho-chloro anilides and thioureas under microwave irradiation. A versatile one pot domino annulation reaction was developed to involve the reaction of benzimidazole linked ortho-chloro amines with acid chlorides and isothiocyanates. The initial acylation and urea formation followed by copper catalyzed intramolecular C-O and C-S cross coupling reactions furnished the angularly oriented bis-heterocycles which bear a close resemblance to the streptomyces antibiotic UK-1.
Novel ionic liquid supported-multicomponent reaction toward chimeric bis-heterocycles
(2012-08-01)
Chen, Chih-Hau
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Chen, Chan-Yu
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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 multicomponent reaction between IL-anchored 2-aminobenzoimidazoles, aldehydes, and electron-deficient dienophiles has been explored. The strategy was utilized to develop a rapid parallel synthesis for novel bis-heterocyclic skeleton of benzimidazole-linked dihydropyrimidine on an ionic liquid support. This multicomponent reaction is compatible with a wide range of substrates and furnishes the new chimeric scaffolds with high purity and excellent yields. Use of the ionic liquid as a soluble support facilitates purification by simple precipitation along with advantages like high loading capacity, homogeneous reaction conditions, and monitoring of the reaction progress by conventional NMR spectroscopy.
Parallel synthesis of 2-sulphanylated bis-benzimidazoles on soluble polymer support
(2008-05-01)
Chang, Chia-Mao
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Kulkarni, Manohar V.
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Chen, Chih-Hau
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Wang, Chi-Hsiang
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Sun, Chung-Ming
A well-sustained multistep synthetic protocol has been designed for the PEG-functionalized aromatic acid amide to generate a molecular library of 2-alkylthio bis-benzimidazoles. An attempted synthesis of benzimidazole-2-thiol in dichloromethane has led to S-chloromethyl methyl sulfides, mimicking bacterial enzymatic systems. Regioselective S-alkylation was brought about under controlled conditions using a mild base at room temperature. The polymer-free compounds, 2-sulfanylated bisbenzimidazoles, were obtained in high yields and high purities. Chemical shift changes in proton and carbon NMR-have been employed to monitor the progress of the reaction steps and to prove the site of S-alkylation, respectively.
Qualitative analysis of the fluorophosphonate-based chemical probes using the serine hydrolases from mouse liver and poly-3-hydroxybutyrate depolymerase (PhaZ) from Bacillus thuringiensis
(2012-11-01)
Huang, Yi-Long
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Chung, Tsai-Wen
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Chang, Chia-Mao
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Chen, Chih-Hau
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Liao, Chen-Chung
The serine hydrolase family consists of more than 200 members and is one of the largest enzyme families in the human genome. Although up to 50 % of this family remains unannotated, there are increasing evidences that activities of certain serine hydrolases are associated with diseases like cancer neoplasia, invasiveness, etc. By now, several activity-based chemical probes have been developed and are applied to profile the global activity of serine hydrolases in diverse proteomes. In this study, two fluorophosphonate (FP)-based chemical probes were synthesized. Further examination of their abilities to label and pull down serine hydrolases was conducted. In addition, the poly-3-hydroxybutyrate depolymerase (PhaZ) from Bacillus thuringiensis was demonstrated as an appropriate standard serine hydrolase, which can be applied to measure the labeling ability and pull-down efficiency of FP-based probes. Furthermore, mass spectrometry (MS) was used to identify the serine residue that covalently bonded to the active probes. Finally, these FP-based probes were shown capable of establishing the serine hydrolase profiles in diverse mouse tissues; the serine hydrolases pulled down from mouse liver organ were further identified by MS. In summary, our study provides an adequate method to evaluate the reactivity of FP-based probes targeting serine hydrolases.
Regioselective Piperidine-Catalyzed Tandem Imination-Isocyanate Annulation to Fused Tricyclic Triazines
(2014-05-01)
Barve, Indrajeet J.
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Chen, Chih-Hau
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Kao, Chih-Hsien
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Sun, Chung-Ming
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應用化學系
A novel tandem imination-isocyanate-mediated annulation was explored. Ionic liquid-immobilized 2-aminobenzimidazoles react sequentially with aldehydes and isocyanates to give highly functionalized benzimidazole-embedded triazines. The second-stage transformation revealed that the formation of triazinone functionality is entirely regioselective to allow rapid assembly of biologically interesting tricyclic skeletons. In conjunction with the application of microwave irradiation and IL support, this method provides an efficient route to access substituted benzoimidazotriazines.
Regioselective, Unconventional Pictet-Spengler Cyclization Strategy Toward the Synthesis of Benzimidazole-Linked Imidazoquinoxalines on a Soluble Polymer Support
(2011-06-06)
Chen, Chih-Hau
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Kuo, Jaren
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Yellol, Gorakh S.
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Sun, Chung-Ming
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應用化學系
A novel strategy for an unconventional Pictet-Spengler reaction has been developed for the regioselective cyclization of the imidazole ring system at the C2 position. The developed strategy was utilized to develop a diversity-oriented parallel synthesis for bis(heterocyclic) skeletal novel analogs of benzimidazole-linked imidazoquinoxalines on a soluble polymer support under microwave conditions. Condensation of polymer-immobilized o-phenylenediamines with 4-fluoro-3-nitrobenzoic acid followed by nucleophilic aromatic substitution with an imidazole motif affords bis(heterocyclic) skeletal precursors for the Pictet-Spengler reaction. The unconventional Pictet-Spengler cyclization with various aldehydes was achieved regioselectively at the C2 position of the imidazole ring to furnish rare imidazole-fused quinoxaline skeletons. During the Pictet-Spengler cyclization, aldehydes bearing electron-donating groups afford 4,5-dihydro-imidazoquinoxalines, which then auto-aromatize into benzimidazole-linked imidazo[1,2-a]quinoxalines. However, interestingly, aldehydes bearing electron-withdrawing groups directly provide aromatized imidazo[1,2-a]quinoxalines, which unexpectedly afford novel benzimidazole-linked 4-methoxy-4,5-dihydro-imidazo[1,2-a] quinoxalines after polymer cleavage.
Scaffold-directed and traceless synthesis of tricyclic quinoxalinone imidazoles under microwave irradiation
(2011-02-01)
Thummanagoti, Suman
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Chen, Chih-Hau
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Xu, Zhan-Hui
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Sun, Chung-Ming
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應用化學系
Traceless synthesis of 2-aminoimidazoquinoxalinones has been performed on soluble polymer support under open-vessel microwave dielectric heating. The reaction progression is monitored directly by the conventional proton NMR which indicated no release of the substrate from the support. Fmoc-deprotected amino acid polymer conjugates react with 1,5-difluoro-2,4-dinitro benzene to yield polymer bound dinitro fluoro amines, which are further substituted by various primary amines to yield PEG-immobilized dinitrodiamines. Simultaneous reduction of aromatic meta-dinitro group leads to the traceless release of 2-quinoxalinones, followed by N-hetero cyclization with various isothiocyanates in the presence of mercury(II)chloride to furnish 2-aminoimidazoquinolinone rings with three points of diversity at rapid pace.
Scaffold-directed traceless synthesis of tetrahydro-beta-carbolinehydantoins
(2007-07-01)
Chen, Chih-Hau
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Chang, Chia-Mao
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Chen, Hsia-Yuan
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Lai, Jin-Ji
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Sun, Chung-Ming
Pharmacologically interesting tetrahydro-beta-carbolinehydantoins have been prepared through four-step traceless synthesis by a combinatorial approach. Two-arm PEG 1 (MW approximate to 4000) was used as a soluble polymer support and reacted with Fmoc-protected L-tryptophane 2 to form bis-ester 3. The resulting polymer-supported amino ester 3 was deprotected, and amino ester 4 underwent Pictet-Spengler reaction with varoius ketones to form tricyclic indoles 5. The nucleophilic piperidine in the tricyclic indole reacted with isocyanate to generate the urea intermediates and simultaneously intramolecular cyclization to release the target compounds 7 from the support in good yields.
Synthesis of structurally diverse benzimidazolyl benzimidazolones by application of soluble polymer support
(2008-06-30)
Chen, Hsia-Yuan
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Kulkarni, Manohar V.
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Chen, Chih-Hau
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Sun, Chung-Ming
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應用化學系
Chemical stability and reactivity of a bifunctional polymer conjugate containing an ortho-amino arylamide linkage have been successfully exploited to achieve a parallel synthesis of methoxycarbonylated head-tail bis-benzimidazoles. Regioselective alkylation of the two nitrogens in the benzimidazolone moiety has been carried out by ipso-fluoro displacement, and N-alkylation to generate two diversities. Cleavage of the polymer support has resulted in two libraries of di- and tri-substituted benzimidazolyl benzimidazolones in high purity and high yield. All reaction steps have been monitored by (1)H NMR on the support directly. (c) 2008 Elsevier Ltd. All rights reserved.