- Application RNA-helicase DHX33 inhibitor in preparation of medicine for treating leukemia
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The invention discloses application of RNA-helicase DHX33 inhibitor in preparation of a medicament for treating or assisting in treating leukemia. The invention establishes an important role DHX33 protein in developing the leukemia, and the provided small molecule compound has the effect of inhibiting DHX33 helicase activity, thereby promoting DHX33 family protein mediated leukemia cancer apoptosis regulated by BCL - 2.
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Paragraph 0092; 0096-0102
(2021/11/10)
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- N-sulfonyl heterocyclic derivative and pharmaceutical application thereof
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The invention discloses an N-sulfonyl heterocyclic derivative and pharmaceutical application thereof. The structure of the N-sulfonyl heterocyclic derivative is shown as a formula I in the specification. Experiments show that the compound provided by the invention can effectively inhibit hepatitis B virus core protein assembly and hepatitis B virus replication. The compound provided by the invention has wide application prospects in preparation of hepatitis B virus core protein assembly inhibitors, anti-hepatitis B virus medicines and medicines for preventing and/or treating hepatitis B virus infection related diseases (such as hepatitis B, liver cirrhosis and liver cancer).
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Paragraph 0107-0110
(2021/04/21)
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- Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity
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The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.
- Mahy, William,Patel, Mikesh,Steadman, David,Woodward, Hannah L.,Atkinson, Benjamin N.,Svensson, Fredrik,Willis, Nicky J.,Flint, Alister,Papatheodorou, Dimitra,Zhao, Yuguang,Vecchia, Luca,Ruza, Reinis R.,Hillier, James,Frew, Sarah,Monaghan, Amy,Costa, Artur,Bictash, Magda,Walter, Magnus W.,Jones, E. Yvonne,Fish, Paul V.
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p. 9464 - 9483
(2020/10/19)
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- Design, synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis
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In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H37Ra with an MIC value of 77 μM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated for in vitro studies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13i, ethyl 1-(4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 μM against Mtb H37Ra, respectively.
- Liu, Pingxian,Yang, Yang,Ju, Yuan,Tang, Yunxiang,Sang, Zitai,Chen, Lijuan,Yang, Tao,An, Qi,Zhang, Tianyu,Luo, Youfu
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p. 422 - 432
(2018/07/14)
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- Urea decomposition: Efficient synthesis of pyrroles using the deep eutectic solvent choline chloride/urea
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A simple and efficient method is reported for the synthesis of pyrroles via condensation of a series of tricarbonyl compounds with ammonia, which was generated in situ from decomposition of the deep eutectic solvent choline chloride/urea.
- Hu, Lanfang,Luo, Juan,Lu, Dan,Tang, Qiang
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supporting information
p. 1698 - 1701
(2018/04/02)
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- Development of Pyridazinone Chemotypes Targeting the PDEδ Prenyl Binding Site
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The K-Ras GTPase is a major target in anticancer drug discovery. However, direct interference with signaling by K-Ras has not led to clinically useful drugs yet. Correct localization and signaling by farnesylated K-Ras is regulated by the prenyl binding protein PDEδ. Interfering with binding of PDEδ to K-Ras by means of small molecules provides a novel opportunity to suppress oncogenic signaling. Here we describe the identification and structure-guided development of novel K-Ras–PDEδ inhibitor chemotypes based on pyrrolopyridazinones and pyrazolopyridazinones that bind to the farnesyl binding pocket of PDEδ with low nanomolar affinity. We delineate the structure–property relationship and in vivo pharmacokinetic (PK) and toxicokinetic (Tox) studies for pyrazolopyridazinone-based K-Ras–PDEδ inhibitors. These findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic Ras.
- Murarka, Sandip,Martín-Gago, Pablo,Schultz-Fademrecht, Carsten,Al Saabi, Alaa,Baumann, Matthias,Fansa, Eyad K.,Ismail, Shehab,Nussbaumer, Peter,Wittinghofer, Alfred,Waldmann, Herbert
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supporting information
p. 6083 - 6093
(2017/05/05)
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- Quinoline derivatives and their use
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The invention discloses a quinoline derivative and a usage thereof, a compound with a structure as shown in a formula (I) and or a pharmaceutically acceptable salt of the compound. The compound or the pharmaceutically acceptable salt thereof disclosed by the invention can be applied to the field of preparation of drugs for preventing or treating tumors.
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Paragraph 0230; 0231; 0232
(2017/03/14)
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- Discovery of novel Tetrahydrobenzo[b]thiophene and pyrrole based scaffolds as potent and selective CB2 receptor ligands: The structural elements controlling binding affinity, selectivity and functionality
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CB2-based therapeutics show strong potential in the treatment of diverse diseases such as inflammation, multiple sclerosis, pain, immune-related disorders, osteoporosis and cancer, without eliciting the typical neurobehavioral side effects of CB1 ligands. For this reason, research activities are currently directed towards the development of CB2 selective ligands. Herein, the synthesis of novel heterocyclic-based CB2 selective compounds is reported. A set of 2,5-dialkyl-1-phenyl-1H-pyrrole-3-carboxamides, 5-subtituted-2-(acylamino)/(2-sulphonylamino)-thiophene-3-carboxylates and 2-(acylamino)/(2-sulphonylamino)-tetrahydrobenzo[b]thiophene-3-carboxylates were synthesized. Biological results revealed compounds with remarkably high CB2 binding affinity and CB2/CB1 subtype selectivity. Compound 19a and 19b from the pyrrole series exhibited the highest CB2 receptor affinity (Ki= 7.59 and 6.15 nM, respectively), as well as the highest CB2/CB1 subtype selectivity (～70 and ～200-fold, respectively). In addition, compound 6b from the tetrahydrobenzo[b]thiophene series presented the most potent and selective CB2 ligand in this series (Ki= 2.15 nM and CB2 subtype selectivity of almost 500-fold over CB1). Compound 6b showed a full agonism, while compounds 19a and 19b acted as inverse agonists when tested in an adenylate cyclase assay. The present findings thus pave the way to the design and optimization of heterocyclic-based scaffolds with lipophilic carboxamide and/or retroamide substituent that can be exploited as potential CB2 receptor activity modulators.
- Osman, Noha A.,Ligresti, Alessia,Klein, Christian D.,Allarà, Marco,Rabbito, Alessandro,Di Marzo, Vincenzo,Abouzid, Khaled A.,Abadi, Ashraf H.
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p. 619 - 634
(2016/07/22)
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- Understanding the Scope of Feist–Bénary Furan Synthesis: Chemoselectivity and Diastereoselectivity of the Reaction Between α-Halo Ketones and β-Dicarbonyl Compounds
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Feist–Bénary furan synthesis, the reaction between α-halocarbonyl and β-dicarbonyl compounds, has been known as an efficient method for generating many different types of furans containing a carbonyl group at C-3. However, it has also been reported that, under similar reaction conditions, intermediate tricarbonyl species could be further converted to alternative furan isomers through the application of a Paal–Knorr synthesis. In this manuscript, we investigate the chemoselectivity and diastereoselectivity of furan synthesis from α-halo ketones and β-dicarbonyl compounds, by carrying out the separation and characterization of the intermediates involved in the reaction. Additionally, a one-pot Feist–Bénary furan synthesis from α-halo ketones and β-dicarbonyl compounds without any base or solvent has also been developed.
- Peng, Yi,Luo, Juan,Feng, Qiang,Tang, Qiang
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p. 5169 - 5179
(2016/10/26)
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- Design, synthesis and antifungal activity of novel furancarboxamide derivatives
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Twenty-seven novel furancarboxamide derivatives with a diphenyl ether moiety were synthesized and evaluated for their antifungal activity against Rhizoctonia solani, Botrytis cirerea, Valsa Mali and Sphaceloma ampelimum. Antifungal bioassay results indicated that most compounds had good or excellent fungicidal activities for R. solani and S. ampelimum at 20 mg L-1. Among synthesized compounds, compound 18e showed a greater inhibitory effect against S. ampelimum, with half maximal effective concentration (EC50) values of 0.020 mg L-1. This strong activity rivals currently used commercial fungicides, such as Boscalid and Carbendazim, and has great potential as a lead compound for future development of novel fungicides.
- Wen, Fang,Jin, Hong,Tao, Ke,Hou, Taiping
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p. 244 - 251
(2016/05/24)
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- Synthesis and biological evaluation of 3-phenyl-3-aryl carboxamido propanoic acid derivatives as small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26A1)
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All-trans-retinoic acid (ATRA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases and cancers. However, it is easily metabolized. In this study, the leading compound S8 was found based on virtual screening. To improve the activity of the leading compound S8, a series of novel S8 derivatives were designed, synthesized and evaluated for their in vitro biological activities. All of the prepared compounds showed that substituting the 5-chloro-3-methyl-1-phenyl-1H-pyrazole group for the 2-tertbutyl-5-methylfuran scaffold led to a clear increase in the biological activity. The most promising compound 32, with a CYP26A1 IC50 value of 1.36 μM (compared to liarozole (IC50 = 2.45 μM) and S8 (IC50 = 3.21 μM)) displayed strong inhibitory and differentiation activity against HL60 cells. In addition, the study focused on the effect of β-phenylalanine, which forms the coordination bond with the heme of CYP26A1. These studies suggest that the compound 32 can be used as an appropriate candidate for future development.
- Zhao, Dongmei,Sun, Bin,Ren, Jinhong,Li, Fengrong,Song, Shuai,Lv, Xuejiao,Hao, Chenzhou,Cheng, Maosheng
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p. 1356 - 1365
(2015/03/04)
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- Pyridazinones for the treatment of cancer
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The present invention relates to novel substituted pyrrolo- and pyrazolopyridazinones, as well as pharmaceutical compositions containing at least one of these substituted pyrrolo- and pyrazolo- pyridazinones together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. Said novel substituted pyrrolo- and pyrazolo- pyridazinones are binding to the prenyl binding pocket of PDEδ and therefore, are useful for the prophylaxis and treatment of cancer by inhibition of the binding of PDEδ to K-Ras and of Ras signaling in cells.
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Page/Page column 0028; 0064-0065
(2015/12/31)
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- BENZYLAMINE DERIVATIVES
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The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R1 to R3, R5 to R9, A, P, V, W, X, Y and Z are as defined herein.
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Page/Page column 36; 38
(2014/07/23)
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- HETEROCYCLIC DERIVATES
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The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R5, R6, R7, A, B,W, X, Y and Z are as defined herein.
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Page/Page column 43
(2014/12/12)
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- Preparation and Reactivities of (η3-1- and 2-Trimethylsiloxyallyl)Fe(CO2)NO Complexes. Intermediates Functioning as Equivalents of β- and α-Acyl Carbocations and Acyl Carbanions
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(η3-1- and 2-Trimethylsiloxyallyl)Fe(CO)2NO complexes were prepared by the reaction of the corresponding siloxyallylic halides with Bu4N.These complexes reacted with both of carbon nucleophiles and carbon electrophiles preferentially at the less hindered sites of the allylic ligands.In these reactions, (η3-1-trimethylsiloxyallyl)Fe(CO)2NO complexes served as synthetically equivalent synthons for both of β-acyl carbocations and β-acyl carbanions and (η3-2-trimethylsiloxyallyl)Fe(CO)2NO complexes as both of α-acyl carbocations and α-acyl carbanions.The stereochemical courses of the reactions are described.
- Itoh, Keiji,Nakanishi, Saburo,Otsuji, Yoshio
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p. 2965 - 2977
(2007/10/02)
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- A NEW SYNTHESIS OF DIHYDROJASMON
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Strictly controlled hydrolysis of 5-methylene-4,5-dihydrofurans 3 allows an efficient approach to 2-acetonyl-1,3-dicarbonyl compounds 4, key intermediates in the synthesis of cyclopentenone derivatives.
- Antonioletti, Roberto,Bonadies, Francesco,Scettri, Arrigo
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p. 233 - 234
(2007/10/02)
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- A Novel Acetonylation of Carbonucleophiles via Palladium-Catalyzed Allylation with Isopropyl 2-Methylene-3,5-dioxahexyl Carbonate
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Carbonucleophiles such as malonate esters, β-keto esters, phenylacetate ester, and phenylacetonitrile were acetonylated in high yields by allylation with isopropyl (or methyl) 2-methylene-3,5-dioxahexyl carbonate (4b or 4a) in the presence of palladium-phosphine catalyst under neutral conditions, followed by acidic hydrolysis.Adopting this procedure dihydrojasmone (7) was prepared from ethyl 3-oxononanoate (6) in an overall yield of 72percent.
- Ikeda, Isao,Gu, Xue-Ping,Okuhara, Toshio,Okahara, Mitsuo
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- SYNTHESIS OF ESTERS OF 2-SUBSTITUTED 4-KETOPENTANOIC ACIDS BY THE ALKYLATION OF CH-ACIDS USING CHLOROACETONE UNDER PHASE TRANSFER CATALYSIS CONDITIONS
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An improved method was developed for the synthesis of ethyl esters of 2-substituted 4-ketopentanoic acids by the alkylation of CH2(X)CO2Et using chloroacetone in the liquid-solid KOH (K2CO3 or Na2CO3)-DMF-PhCH2(Et)3NCl system.
- Sizov, A. Yu.,Yanovskaya, L. A.,Dombrovskii, V. A.
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p. 410 - 411
(2007/10/02)
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- THE SYNTHESIS AND CHEMISTRY OF AZOLENINES. PART 18. PREPARATION OF 3-ETHOXYCARBONYL-3H-PYRROLES VIA THE PAAL-KNORR REACTION, AND SIGMATROPIC REARRANGEMENTS INVOLVING COMPETITIVE ESTER MIGRATIONS TO C-2, C-4 AND N.
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3H-Pyrrole-3-carboxylic esters (4) have been prepared, in some cases together with isomers (5) and (6) having exocyclic double bonds, by cyclization of suitably substituted 2-ethoxycarbonyl-1,4-diketones (1) with liquid ammonia, followed by dehydration of the isolable 2-hydroxy-3,4-dihydro-2H-pyrrole intermediates (2) and (3) with aluminia in boiling solvents.Prolonged heating in toluene or p-xylene converts the 3H-pyrroles (4) quantitatively into isomeric 4-esters (11) and N-esters (13) of 1H-pyrroles via competitive sigmatropic rearrangements.Isolable intermediate 2H-pyrrole-2-carboxylic esters (12) are converted similarly into the same products, under the same conditions.Detection of 3H-pyrroles (4) as intermediates in the latter reaction demonstrates for the first time the reversibility of the thermal 2H-pyrrole to 3H-pyrrole interconversion.
- Chiu, Pak-Han,Sammes, Michael P.
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p. 3439 - 3456
(2007/10/02)
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- 2-(Chloromethyl)-3,5-dioxahex-1-ene. An Effective Acetonylating Reagent
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By β-elimination of 2-chloro-1-(chloromethyl)ethyl methoxymethyl ether (1) under solid-liquid phase-transfer catalytic conditions, 2-(chloromethyl)-3,5-dioxahex-1-ene (2) of high purity was readily obtained in 85percent.Allyl chloride (2) is found to be stable at ambient conditions and to be a superior reagent as CH3COCH2+ synthon for converting active proton-containing compounds such as carboxylic acids, amines, phenols, alcohols, thiols, malonate, β-diketones, β-keto esters, phenylacetonitrile, fluorene, and indene to the corresponding acetonyl derivatives in good to excellent yields (61-93percent), usually under phase-transfer catalytic conditions or in a t-BuONa-t-BuOH system.
- Gu, Xue-Ping,Nishida, Nobuyuki,Ikeda, Isao,Okahara, Mitsuo
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p. 3192 - 3196
(2007/10/02)
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- Furan-3-carboxamide derivatives and method of preparing same
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A broad class of furan-3-Carboxamide derivatives, including many novel compounds, can be made reliably and in good yields by a novel one step reaction between an α-hydroxyketone and an acetamide in the presence of a Friedel-Crafts agent in an inert solvent. The broad class of derivatives has fungicidal and insecticidal utility.
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