- Discovery of novel inhibitors of human phosphoglycerate dehydrogenase by activity-directed combinatorial chemical synthesis strategy
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Serine, the source of the one-carbon units essential for de novo purine and deoxythymidine synthesis plays a crucial role in the growth of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first, rate-limiting step in de novo serine biosynthesis has become a promising target for the cancer treatment. Here we identified H-G6 as a potential PHGDH inhibitor from the screening of an in-house small molecule library based on the enzymatic assay. We adopted activity-directed combinatorial chemical synthesis strategy to optimize this hit compound. Compound b36 was found to be the noncompetitive and the most promising one with IC50 values of 5.96 ± 0.61 μM against PHGDH. Compound b36 inhibited the proliferation of human breast cancer and ovarian cancer cells, reduced intracellular serine synthesis, damaged DNA synthesis, and induced cell cycle arrest. Collectively, our results suggest that b36 is a novel PHGDH inhibitor, which could be a promising modulator to reprogram the serine synthesis pathway and might be a potential anticancer lead worth further exploration.
- Zhou, Xia,Tan, Yuping,Gou, Kun,Tao, Lei,Luo, Yuan,Zhou, Yue,Zuo, Zeping,Sun, Qingxiang,Luo, Youfu,Zhao, Yinglan
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- Enantioselective Synthesis of Spiropyrazolone-Fused Cyclopenta[ c]chromen-4-ones Bearing Five Contiguous Stereocenters via (3+2) Cycloaddition
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An enantioselective synthesis of spiropyrazolone-fused cyclopenta[c]chromen-4-ones is demonstrated via a (3+2) cycloaddition reaction. The reactions of 3-homoacylcoumarins and α,β-unsaturated pyrazolones in the presence of the cinchona-alkaloid derived hy
- Khairnar, Pankaj V.,Su, Yin-Hsiang,Edukondalu, Athukuri,Lin, Wenwei
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p. 12326 - 12335
(2021/08/24)
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- A three-component, general and practical route for diastereoselective synthesis of aza-spirocyclic pyrazolonesviaa decarboxylative annulation process
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An efficient, general, and practical route for highly diastereoselective synthesis of aza-spirocyclic pyrazolones from easily available α-amino acids, aldehydes, and alkylidene pyrazolones by means of a decarboxylative annulation process is reported. This
- Awasthi, Annapurna,Yadav, Pushpendra,Tiwari, Dharmendra Kumar
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p. 2374 - 2383
(2021/02/16)
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- Organophosphane-catalyzed direct β-acylation of 4-arylidene pyrazolones and 5-arylidene thiazolones with acyl chlorides
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An efficient method for the direct β-acylation of arylidene pyrazolones and thiazolones with acyl chlorides in the presence of a base catalyzed by organophosphanes is reported. A variety of functionalized 4-arylidene pyrazolone and 5-arylidene thiazolone derivatives were prepared under metal-free and mild conditions via a tandem phospha-Michael addition/O-acylation/intramolecular cyclization/rearrangement sequence. Our mechanistic investigations revealed that the reaction is highly stereospecific to provide exclusively cis-isomers, and the methodology can also be scaled up with similar efficacy.
- Khairnar, Pankaj V.,Su, Yin-Hsiang,Chen, Yung-Chang,Edukondalu, Athukuri,Chen, Yi-Ru,Lin, Wenwei
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p. 6868 - 6872
(2020/09/15)
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- Enantio- and Diastereoselective Synthesis of β-Aryl-β-pyrazolyl α-Amino Acid Esters via Copper-Catalyzed Reaction of Azomethine Ylides with Benzylidenepyrazolones
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A fully stereoselective synthesis of unnatural chiral β-aryl-β-pyrazolyl α-amino acid esters via copper-catalyzed addition reactions of azomethine ylides with benzylidenepyrazolones bearing two contiguous stereogenic centers was developed. A 1H-pyrazol-5-ol was introduced by the aromatization of 3H-pyrazol-3-one in the reaction. The transformation operated at room temperature and afforded β-1H-pyrazol-5-ol-α-amino esters in high yields with good to excellent levels of diastereo- and enantioselectivity.
- Gong, Yan-Chuan,Wang, Yue,Li, Er-Qing,Cui, Hao,Duan, Zheng
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supporting information
(2019/02/07)
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- Enantio- And diastereoselective synthesis of b-Aryl-b-pyrazolyl a-amino acid esters via copper-catalyzed reaction of azomethine ylides with benzylidenepyrazolones
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A fully stereoselective synthesis of unnatural chiral b-aryl-b-pyrazolyl a-amino acid esters via copper-catalyzed addition reactions of azomethine ylides with benzylidenepyrazolones bearing two contiguous stereogenic centers was developed. A 1H-pyrazol-5-ol was introduced by the aromatization of 3H-pyrazol-3-one in the reaction. The transformation operated at room temperature and afforded b-1H-pyrazol-5-ol-a-amino esters in high yields with good to excellent levels of diastereo- and enantioselectivity.
- Gong, Yan-Chuan,Wang, Yue,Li, Er-Qing,Cui, Hao,Duan, Zheng
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supporting information
p. 1389 - 1393
(2019/10/28)
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- Tosylmethylisocyanide (TosMIC) [3+2] cycloaddition reactions: A facile Van Leusen protocol for the synthesis of the new class of spirooxazolines, spiropyrrolines and Chromeno[3,4-c]pyrrols
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The reactivity and chemo-, regio- and diastreo-selectivity of tosylmethyl isocyanides (TosMIC) are investigated in Van Leusen type [3 + 2] cycloaddition reactions with the various activate cyclic ketones and double C–C bonds in the synthesis of spirooxazolines, spiropyrrolines and chromeno[3,4-c]pyrrols in good to excellent yields under catalyst-free conditions without any activation at ambient temperature.
- Shaabani, Ahmad,Sepahvand, Heshmatollah,Bazgir, Ayoob,Khavasi, Hamid Reza
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p. 7058 - 7067
(2018/11/02)
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- Lewis-Base-Catalyzed [1 + 2 + 2] Annulation Reaction of Morita-Baylis-Hillman Carbonates with Unsaturated Pyrazolones: Construction of All-Stereogenic Carbon Cyclopentane-Fused Dispiropyrazolones
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The first Lewis-base-catalyzed unexpected [1 + 2 + 2] annulation reaction between Morita-Baylis-Hillman carbonates and unsaturated pyrazolones was developed. The multicyclic cyclopentane-fused dispiropyrazolone constructions containing five contiguous ste
- Liang, Jin-Yan,Shen, Shou-Jie,Chai, Xiao-Qian,Lv, Ting
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p. 12744 - 12752
(2018/10/09)
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- Organocatalytic Asymmetric Michael/Hemiketalization/Retro-aldol Reaction of α-Nitroketones with Unsaturated Pyrazolones: Synthesis of 3-Acyloxy Pyrazoles
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An organocatalytic asymmetric cascade Michael/hemiketalization/retro-aldol reaction between unsaturated pyrazolones and α-nitroketones is described. A bifunctional thiourea catalyst was found to be efficient for this reaction. With 10 mol % of catalyst, high yields as well as excellent enantioselectivities are attained for a variety of 3-acyloxy pyrazoles under mild reaction conditions.
- Maity, Rajendra,Gharui, Chandan,Sil, Arun K.,Pan, Subhas Chandra
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p. 662 - 665
(2017/02/10)
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- Palladium N-heterocyclic carbene catalyzed expected and unexpected C-C and C-N functionalization reactions of 1-aryl-3-methyl-1: H -pyrazol-5(4 H)-ones
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A palladium N-heterocyclic carbene [Pd(NHC)Cl2] complex of vitamin B1 developed earlier in our laboratory was successfully employed as an efficient catalyst for the regioselective C-C and C-N functionalization reactions of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones 1a-b. The catalyst was attempted for the C-H arylation, acylation and alkoxylation of 1a-b using the respective coupling substrates such as aryl iodides 2a-c, benzylic alcohols 3a-d and methanol/ethanol 4. It was surprisingly noted that the acylation and alkoxylation reactions underwent a diverse pathway to yield some unexpected products rather than the targeted ones. In the case of the arylation reactions only the targeted products have been observed. This has made the protocol very interesting compared to the conventional coupling reactions.
- Purohit, Vishal B.,Karad, Sharad C.,Patel, Kirit H.,Raval, Dipak K.
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p. 111139 - 111143
(2016/12/07)
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- An asymmetric approach toward chiral multicyclic spirooxindoles from isothiocyanato oxindoles and unsaturated pyrazolones by a chiral tertiary amine thiourea catalyst
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The first organocatalytic Michael-cyclization cascade reaction between isothiocyanato oxindoles and unsaturated pyrazolones has been developed. The multicyclic spiro[oxindole/thiobutyrolactam/pyrazolone] core structures containing three contiguous stereog
- Chen, Qiao,Liang, Jinyan,Wang, Shoulei,Wang, Dong,Wang, Rui
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p. 1657 - 1659
(2013/03/14)
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- Ionic liquid-mediated facile synthesis of novel spiroheterobicyclic rings as potential antifungal and antibacterial drugs
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A pseudo four-component reaction of urea or thiourea, diverse aryl aldehydes, and 3-methyl-1-phenyl-2-pyrazolin-5-one in ionic liquids yields novel azaspiro[4.5]decene derivatives. However, the corresponding reaction in volatile organic solvents gives Kno
- Dandia, Anshu,Jain, Anuj K.
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p. 104 - 113
(2013/04/10)
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- Regioselective synthesis of diltiazem analogue pyrazolo[4,3-c][1,5] benzothiazepines and antifungal activity
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A dry media procedure has been developed for the synthesis of a series of new class of pyrazolo [4,3-c][1,5]benzothiazepines 6 under microwave irradiation using montmorillonite K10 as solid support. The catalyst can be recovered and reused. Thus, the procedure provides a simple and green synthetic methodology under environmentally friendly conditions. Antifungal screening of synthesized compounds has shown promising activity. Supplemental materials are available for this article. Go to the publishers online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Taylor & Francis Group, LLC.
- Dandia, Anshu,Singh, Ruby,Singh, Dharmendra,Laxkar, Ashok,Sivpuri, Asha
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experimental part
p. 2472 - 2479
(2011/02/23)
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- Three-component reaction to form 1,4-dihydropyrano[2,3-c]pyrazol-5-yl cyanides
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The three-component reactions of 3-alkyl-1-phenyl-2-pyrazolin-5-ones, aryl aldehydes, and malononitrile in the presence of base catalysts such as sodium acetate, triethylamine, and magnesium oxide (MgO) are investigated. Magnesium oxide (MgO) effectively
- Sheibani, Hassan,Babaie, Maryam
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experimental part
p. 257 - 265
(2010/03/30)
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- Highly stereoselective construction of spiro[cyclopropane-1,4′-pyrazolin-5′-one]with 4-arylidene-3-methyl-1-phenyl-pyrazolin-5-one and arsonium ylide
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A highly stereoselective synthesis of exo-spiro[cyclopropane-1,4′-pyrazolin-5′-one] from 4-arylidene-3-methyl-1-phenyl-pyrazolin-5-one and arsonium bromide in the presence of base has been achieved. The triphenylarsine-catalyzed cyclopropanation of 4-arylidene-3-methyl-1-phenyl-pyrazolin-5-one with bromide in the presence of NaHCO3 has also been studied. Both exo and endo isomers were formed in this reaction. The structures of the products were characterized by IR, MS, 1H NMR, elemental analysis, and X-ray diffraction analysis.
- Ren, Zhongjiao,Cao, Weiguo,Chen, Jie,Chen, Yali,Deng, Hongmei,Shao, Min,Wu, Danyi
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p. 5156 - 5161
(2008/09/21)
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- LiBr catalyzed, microwave enhanced synthesis of 5-arylidene rhodanine under solvent free conditions
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A variety of aldehydes are condensed with rhodaninc under solvent free conditions using LiBr affording 5-arylidene rhodanines in excellent yields. Also this reaction protocol in extendable to other related systems like pyrazol-5-one and 2,4-thiazolidinedi
- Saini, Anil,Bhatti, Ravinder S.,Sandhu, Jagir S.
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experimental part
p. 1239 - 1241
(2009/12/31)
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- Utility of 1-(2,4-dimethoxyphenyl)-3-aryl-prop-2-ene-1-ones as ring transformer in preparing heterocyclic compounds and their potential biological activities
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As an effort to synthesize new heterocyclic compounds, which would be expected to have a pharmacological and biological activities, we report here the reactivity of 1-(2,4-dimethoxyphenyl)-3-aryl-2-propen-1-ones (Ia&b), as Michael acceptors under differen
- Salem,Soliman,Smith,Mahmoud,Azab
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- KF-Al2O3 catalyzed the condensations of 2-methylbenzoxazole and pyrazol-5-one with aromatic aldehydes
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In the presence of KF-Al2O3 as a solid base, 2-methylbenzoxazole 1 in DMF and 1-phenyl-3-methylpyrazol-5-one 2 in methanol, respectively, reacted with aromatic aldehydes to give 2-styrylbenzoxazoles 4a-f in high yields and 1-phenyl-3
- Sun,Yan,Han
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p. 151 - 154
(2007/10/03)
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- New Aspects in the Reaction of Azomethines with Cyclic CH-Acidic Compounds
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Treatment of substituted benzylidene anilines 1a - f with cyclic CH-acidic compounds 2a - m in ethanol at room temperature yields in addition/elimination reactions the corresponding arylidene derivatives 4 and the 2:1 adducts 5.The addition products 3, which are formed as intermediates, could not be isolated in any case.The donor/acceptor effect of the substituents on the benzylidene moiety influences to a significant extent the reactivity towards the azomethine carbon. Keywords.Azomethine; CH-Acidic compound; Addition/elimination reaction.
- Hennig, Lothar,Alva-Astudillo, Mario,Mann, Gerhard,Kappe, Thomas
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p. 571 - 580
(2007/10/02)
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- Investigations on the Hydrolytic Stability of 4-Arylmethylidene-2-pyrazolin-5-ones
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The 4-Arylmethylidene-2-pyrazoline-5-ones S are not stable under aqueous alkaline conditions.By the substitution of R3 with electron donor substituents S reacts preferably yielding aldehyde A and 2-pyrazoline-5-one P, while with electron acceptor substituents S forms 4,4'-arylmethylidene-bis-2-pyrazoline-5-one B.The intermediate of hydrolysis is 4-(arylhydroxymethyl)-2-pyrazoline-5-one SOH.The second order rate constants of the reactions of S with hydroxidions and with 2-pyrazoline-5-ones P(-) are determined.The dependence of the hydrolytic decomposition of S on the pH value, substituents and temperature is suitable for the intermediate formation of SOH.
- Fanghaenel, E.,Akhlaq, M. S.,Grossmann, N.
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p. 209 - 219
(2007/10/02)
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- Oxopyrazoline-spiro-oxirans. A New Class of Reactive Heterocycles
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Chemical and spectral properties of a series of 1-oxa-5,6-diazaspirohept-6-en-4-ones, synthesized by the oxidation of 4-alkylidene- or 4-arylidene-1-aryl-2-pyrazolin-5-ones are reported
- Ege, Seyhan N.,Adams, Alan. D.,Gess, E. Joseph,Ragone, Katherine S.,Kober, Brian J.,et al.
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p. 325 - 332
(2007/10/02)
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- ADDITION OF HETEROCYCLIC CH ACIDS TO THE C=N BOND OF AZOMETHINES
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The aminomethylation of oxindole, 1-phenyl-3-methyl-5-pyrazolone, and N-phenylrhodanine was studied.Derivatives of these CH acids were obtained as a result of aminomethylation.The addition products were subjected to acid and base hydrolysis; the correspon
- Pavlenko, N. I.,Marshtupa, V. P.,Klyuev, N. A.,Baskunov, B. P.
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p. 808 - 812
(2007/10/02)
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