- Novel Aryl-Substituted Pyrimidones as Inhibitors of 3-Mercaptopyruvate Sulfurtransferase with Antiproliferative Efficacy in Colon Cancer
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The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is one of the more recently identified mammalian sources of H2S. A recent study identified several novel 3-MST inhibitors with micromolar potency. Among those, (2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one) or HMPSNE was found to be the most potent and selective. We now took the central core of this compound and modified the pyrimidone and the arylketone sides independently. A 63-compound library was synthesized; compounds were tested for H2S generation from recombinant 3-MST in vitro. Active compounds were subsequently tested to elucidate their potency and selectivity. Computer modeling studies have delineated some of the key structural features necessary for binding to the 3-MST's active site. Six novel 3-MST inhibitors were tested in cell-based assays: they exerted inhibitory effects in murine MC38 and CT26 colon cancer cell proliferation; the antiproliferative effect of the compound with the highest potency and best cell-based activity (1b) was also confirmed on the growth of MC38 tumors in mice.
- Bantzi, Marina,Augsburger, Fiona,Loup, Jérémie,Berset, Yan,Vasilakaki, Sofia,Myrianthopoulos, Vassilios,Mikros, Emmanuel,Szabo, Csaba,Bochet, Christian G.
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p. 6221 - 6240
(2021/05/06)
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- Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange Reaction
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A Ni-catalyzed aryl sulfide synthesis through an aryl exchange reaction between aryl sulfides and a variety of aryl electrophiles was developed. By using 2-pyridyl sulfide as a sulfide donor, this reaction achieved the synthesis of aryl sulfides without using odorous and toxic thiols. The use of a Ni/dcypt catalyst capable of cleaving and forming aryl-S bonds was important for the aryl exchange reaction between 2-pyridyl sulfides and aryl electrophiles, which include aromatic esters, arenol derivatives, and aryl halides. Mechanistic studies revealed that Ni/dcypt can simultaneously undergo oxidative additions of aryl sulfides and aromatic esters, followed by ligand exchange between the generated aryl-Ni-SR and aryl-Ni-OAr species to furnish aryl exchanged compounds.
- Isshiki, Ryota,Kurosawa, Miki B.,Muto, Kei,Yamaguchi, Junichiro
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supporting information
p. 10333 - 10340
(2021/07/21)
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- Nickel-Catalyzed Deaminative Acylation of Activated Aliphatic Amines with Aromatic Amides via C-N Bond Activation
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Deaminative functionalization of aliphatic primary amines has great synthetic utility. Herein, we describe a Ni-catalyzed reductive deaminative cross-electrophile coupling reaction between Katritzky salts and aromatic amides. This work provides examples of the synthesis of various ketones from alkylpyridinium salts, including both primary and secondary alkylamines. Given its mild reaction conditions and high functional group tolerance, this cross-coupling strategy is expected to be useful for late-stage functionalization of complex compounds.
- Yu, Chu-Guo,Matsuo, Yutaka
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supporting information
p. 950 - 955
(2020/02/15)
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- Copper-mediated C–H thiolation of (hetero)arenes using weakly coordinating directing group
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We have developed a copper-mediated C–H thiolation of (hetero)arenes by using monodentate amide as weakly coordinating directing group. This protocol features excellent functional group tolerance and shows satisfactory compatibility with various heterocycles, such as indole, pyrrole, imidazole, pyridine, thiophene and quinoline. The robust nature of this protocol renders that it has potential value in the synthetic application.
- Wu, Peng,Cheng, Tai-Jin,Lin, Hai-Xia,Xu, Hui,Dai, Hui-Xiong
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supporting information
(2020/06/17)
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- Heterocyclic compound and preparation and application thereof
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The invention relates to bromodomain inhibitors, and provides a compound represented by a general formula I, a pharmaceutically acceptable salt, an enantiomer, a diastereoisomer, an atropisomer, a racemate, a polymorph, a solvate or an isotope-labeled compound (including deuterium substitution) thereof, a preparation method thereof, a pharmaceutical composition containing the same, and applicationthereof in pharmacy.
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Paragraph 0231-0233
(2020/07/24)
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- Controllable phosphorylation of thioesters: Selective synthesis of aryl and benzyl phosphoryl compounds
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The controllable phosphorylations of thioesters were developed. When the reaction was catalyzed by a palladium catalyst, aryl or alkenyl phosphoryl compounds were generated through decarbonylative coupling, while the benzyl phosphoryl compounds were produced through deoxygenative coupling when the reaction was carried out in the presence of only a base.
- Xu, Kaiqiang,Liu, Long,Li, Zhaohui,Huang, Tianzeng,Xiang, Kang,Chen, Tieqiao
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p. 14653 - 14663
(2020/12/29)
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- ORGANIC ELECTROLUMINESCENT COMPOUND AND ORGANIC ELECTROLUMINESCENT DEVICE THEREOF
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Disclosed is an organic EL device comprising an electron buffer material, and a first electrode, a second electrode opposing the first electrode, a light-emitting layer disposed between the two electrodes, and an electron transport zone and an electron bu
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Page/Page column 17
(2017/10/11)
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- Discovery, Structure-Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4
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The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound 60 a close analogue of compound 40 with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound 60 (PXT002331, now foliglurax) was nominated as a candidate for clinical development.
- Charvin, Delphine,Pomel, Vincent,Ortiz, Millan,Frauli, Mélanie,Scheffler, Sophie,Steinberg, Edith,Baron, Luc,Deshons, Laurène,Rudigier, Rachel,Thiarc, Delphine,Morice, Christophe,Manteau, Baptiste,Mayer, Stanislas,Graham, Danielle,Giethlen, Bruno,Brugger, Nadia,Hédou, Ga?l,Conquet, Fran?ois,Schann, Stephan
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supporting information
p. 8515 - 8537
(2017/11/03)
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- ORGANIC ELECTROLUMINESCENT COMPOUND AND ORGANIC ELECTROLUMINESCENT DEVICE COMPRISING THE SAME
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The present invention relates to an organic EL device comprising an electron buffer material, and a first electrode, a second electrode opposing the first electrode, a light-emitting layer disposed between the two electrodes, and an electron transport zon
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Page/Page column 19
(2016/12/26)
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- Chelation-Assisted Nickel-Catalyzed Oxidative Annulation via Double C-H Activation/Alkyne Insertion Reaction
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A nickel/NHC system for regioselective oxidative annulation by double C-H bond activation and concomitant alkyne insertion is described. The catalytic reaction requires a bidentate directing group, such as an 8-aminoquinoline, embedded in the substrate. Various 5,6,7,8-tetrasubstituted-N-(quinolin-8-yl)-1-naphthamides can be prepared as well as phenanthrene and benzo[h]quinoline amide derivatives. Diarylalkynes, dialkylalkynes, and arylalkylalkynes can be used in the system. A Ni0/NiII catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two-component coupling partner and as a hydrogen acceptor. In two shakes: Oxidative annulation by a double C-H activation/alkyne insertion reaction was achieved by a nickel/NHC system. A Ni0/NiII catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two-component coupling partner and as a hydrogen acceptor.
- Misal Castro, Luis C.,Obata, Atsushi,Aihara, Yoshinori,Chatani, Naoto
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supporting information
p. 1362 - 1367
(2016/01/25)
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- CERTAIN TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES, COMPOSITIONS THEREOF AND METHODS OF USE THEREFOR
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Provided are certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor.
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Page/Page column 20-21
(2012/10/08)
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- NOVEL DIHYDROPYRIMIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 156
(2011/04/24)
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- PESTICIDAL CARBOXAMIDES
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To provide novel carboxamides which exhibit an excellent pesticidal activity as pesticides. Carboxamides represented by the following Formula (I) and use thereof as pesticides and an animal parasite control agent wherein each substituent is as defined in
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Page/Page column 75
(2011/02/24)
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- CERTAIN TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES, COMPOSITIONS THEREOF AND METHODS OF USE THEREFOR
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Provided are certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor.
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Page/Page column 35
(2011/07/30)
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- Potent and selective inhibitors of breast cancer resistance protein (ABCG2) derived from the p-glycoprotein (ABCB1) modulator tariquidar
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The efflux pumps ABCB1 (p-gp, MDR1) and ABCG2 (BCRP) are expressed to a high extent by endothelial cells at the blood-brain barrier (BBB) and other barrier tissues and are involved in drug resistance of tumor (stem) cells. Whereas numerous ABCB1 inhibitors are known, only a few ABCG2 modulators with submicromolar activity have been published. Starting from tariquidar (4) analogues as ABCB1 modulators, minimal structural modifications resulted in a drastic shift in favor of ABCG2 inhibition. Highest potency was found when the 3,4-dimethoxy-2-(quinoline-3-carbonylamino)benzoyl moiety in 4 was replaced with a 4-methoxycarbonylbenzoyl moiety bearing a hetarylcarboxamido group in 3-position, e.g., quinoline-3-carboxamido (5,IC50: 119 nM) or quinoline-2-carboxamido (6,IC50: 60 nM, flow cytometric mitoxantrone efflux assay, topotecan-resistant MCF-7 breast cancer cells); the selectivity for ABCG2 over ABCB1 was about 100-500 fold and the compounds were inactive at ABCC2 (MRP2). Chemosensitivity assays against MCF-7/Topo cells revealed that the nontoxic inhibitor 6 completely reverted ABCG2-mediated topotecan resistance at concentrations > 100 nM, whereas 5 showed ABCG2 independent cytotoxicity. ABCG2 inhibitors might be useful for cancer treatment with respect to reversal of multidrug resistance, overcoming the BBB and targeting of tumor stem cells.
- Kühnle, Matthias,Egger, Michael,Müller, Christine,Mahringer, Anne,Bernhardt, Güther,Fricker, Gert,K?nig, Burkhard,Buschauer, Armin
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supporting information; experimental part
p. 1190 - 1197
(2010/03/01)
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- Discovery of a potent class I selective ketone histone deacetylase inhibitor with antitumor activity in vivo and optimized pharmacokinetic properties
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The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclinical species, has a clean off-target profile, and is negative in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.
- Kinzel, Olaf,Llauger-Bufi, Laura,Pescatore, Giovanna,Rowley, Michael,Schultz-Fademrecht, Carsten,Monteagudo, Edith,Fonsi, Massimiliano,Paz, Odalys Gonzalez,Fiore, Fabrizio,Steinkühler, Christian,Jones, Philip
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supporting information; experimental part
p. 3453 - 3456
(2010/03/05)
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- CONDENSED IMIDAZOLE COMPOUND AND USE THEREOF
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The present invention relates to a compound represented by the formula [I] wherein X1, X2 and X3 are each an optionally substituted CH or a nitrogen atom, and any one of X1, X2 and X3 is a nitrogen atom, X4 is an optionally substituted CH, R1 is an optionally substituted phenyl group or an optionally substituted heterocyclic group, and R2 is an optionally substituted pyridin-4-yl group, an optionally substituted pyridine-N-oxide-4-yl group or an optionally substituted pyrimidin-4-yl group, or a salt thereof. The compound has superior p38 MAP kinase inhibitory activity and MMP-13 production inhibitory activity, and is useful as an agent for the prophylaxis or treatment and the like of an inflammatory disease, an autoimmune disease, a debilitating disease, an osteoarticular degenerative disease, a neurodegenerative disease, a vascular disease, a neoplastic disease or an infectious disease.
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Page/Page column 135
(2010/11/28)
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- Design of novel nicotinic ligands through 3D database searching
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A series of quinoline derivatives have been designed on the basis of results from a 3D search of the Cambridge Structural Database using the nicotinic pharmacophore as a query and further modified using molecular modeling. Some of the synthesized compound
- Guandalini, Luca,Martini, Elisabetta,Dei, Silvia,Manetti, Dina,Scapecchi, Serena,Teodori, Elisabetta,Romanelli, M. Novella,Varani, Katia,Greco, Giovanni,Spadola, Loredana,Novellino, Ettore
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p. 799 - 807
(2007/10/03)
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- AMIDE DERIVATIVES WHICH ARE USEFUL AS CYTOKINE INHIBITORS
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The invention concerns amide derivatives of the Formula (I)wherein Ris (1-6C)alkyl or halogeno; Q is aryl or heteroaryl which optionally bears 1, 2, 3 or 4 substituents such as hydroxy, halogeno, trifluoromethyl, cyano, (1-6C)alkyl, (1-6C)alkoxy, halogeno(1-6C)alkyl, hydroxy-(1-6C)alkyl, di-[(1-6C)alklyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkoxy, (1-6)alkoxy-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, amino-2(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, aryl, aryl-(1-6C)alkoxy, heteroaryl, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy; p is 0-2 and Ris a substituent such as hydroxy and halogeno; q is 0-4; and Rincludes optionally substituted aryl, cycloalkyl, heteroaryl and heterocyclyl; or pharmaceutically-acceptable salts or in-vivo-cleavable esters thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.
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- Sulfonamide compounds and medicinal use thereof
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A sulfonamide compound of the formula (I):R 1 --SO 2 NHCO--A--R 2 (I)wherein R 1 is alkyl, alkenyl, alkynyl and the like; A is an optionally substituted heteropolycyclic group except benzimidazolyl, indolyl, 4,7-dihydrobenzimidazolyl and 2,3-dihydrobenzoxazinyl; X is alkylene, oxa, oxa(lower)alkylene and the like; and R 2 is optionally substituted aryl, substituted biphenylyl and the like, a salt thereof and a pharmaceutical composition comprising the same. The sulfonamide compound is effective for the diseases treatable based on their blood sugar level-depressing activity, cGMP-PDE (especially PDE-V)-inhibiting activity, smooth muscle relaxing activity, bronchodilating activity, vasodilating activity, smooth muscle cell suppressing activity, and antiallergic activity.
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Page column 42
(2010/02/04)
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- Aminoalkylindoles: Structure - Activity Relationships of Novel Cannabinoid Mimetics
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Aminoalkylindoles (AAIs) are a novel series of cannabinoid receptor ligands.In this report we disclose the structural features of AAIs which are important for binding to this receptor as measured by inhibition of binding of 3H>Win 55212-2 (5).Functional activity in the mouse vas deferens is also noted and used to distinguish agonists from potential antagonists.The key structural features for potent cannabinoid activity in this series are a bicyclic (naphthyl) substituent at the 3-position, a small (H) substituent at the 2-position, and an aminoethyl (morpholinoethyl) substituent at the 1-position.A 6-bromo analog, Win 54461 (31), has been identified as a potential cannabinoid receptor antagonist.Modeling experiments were done to develop a pharmacophore and also to compare AAI structures with those of classical cannabinoids.The fact that the cannabinoid AAIs arose out of work on a series of cyclooxygenase inhibitors makes sense now that an endogenous cannabinoid ligand has been identified which is a derivative of arachidonic acid.Because of their unique structures and physical properties, AAIs provide useful tools to study the structure and function of the cannabinoid receptor(s).
- Eissenstat, Michael A.,Bell, Malcolm R.,D'Ambra, Thomas E.,Alexander, E. John,Daum, Sol J.,et al.
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p. 3094 - 3105
(2007/10/02)
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