- Discovery of 3,5-Dimethyl-4-Sulfonyl-1 H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability
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Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure-activity relationship study of 3,5-dimethyl-4-sulfonyl-1H-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound 11 with primary Mcl-1 inhibition (52%@30 μM) led to the discovery of the most potent compound 40 with high affinity (Kd = 0.23 nM) and superior selectivity over other Bcl-2 family proteins (>40,000 folds). Mechanistic studies revealed that 40 could activate the apoptosis signal pathway in an Mcl-1-dependent manner. 40 exhibited favorable physicochemical properties and pharmacokinetic profiles (F% = 41.3%). Furthermore, oral administration of 40 was well tolerated to effectively inhibit tumor growth (T/C = 37.3%) in MV4-11 xenograft models. Collectively, these findings implicate that compound 40 is a promising antitumor agent that deserves further preclinical evaluations.
- Zhu, Peng-Ju,Yu, Ze-Zhou,Lv, Yi-Fei,Zhao, Jing-Long,Tong, Yuan-Yuan,You, Qi-Dong,Jiang, Zheng-Yu
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p. 11330 - 11353
(2021/08/24)
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- Substituted Benzothietes: Synthesis and a Quantum Chemical Investigation of Their Cycloreversion Properties
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A flexible synthesis for highly substituted benzothietes that does not require flash-vacuum pyrolysis was developed. This allows for the use of a number of functional groups and nonvaporizable molecules. Highly stabilized derivatives were isolated. The molecular orbital properties of various benzothietes were evaluated by density functional methods. The mechanism of the cycloreversion of the four-membered ring was compared to that of the oxygen-containing analogues.
- Ahlburg, Nils L.,Velarde, Andres R.,Kieber-Emmons, Matthew T.,Jones, Peter G.,Werz, Daniel B.
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supporting information
p. 4255 - 4260
(2020/06/04)
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- SINGLE-STEP SYNTHESIS METHOD OF ARYL THIOL AND APPLICATION THEREOF
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The present invention relates to a single-step synthesis method of aryl thiol, and more specifically, to a method of synthesizing aryl thiol in a single-step by making aryl halide react with alkane dithiol in the presence of a transition metal catalyst. According to the present invention, a single-step synthesis method using the transition metal catalyst, the synthesis method which is capable of synthesizing aryl thiol from aryl halide at a high yield, can be provided. Various aryl halides may be applied to the synthesis method. Further, the synthesis method has advantages that an easily usable reagent may be used, operations are simple, and reactions can be performed under mild conditions. In addition, the synthesized aryl thiol may be used in the synthesis of advanced molecules such as diaryl sulfides and benzothiophenes.COPYRIGHT KIPO 2017
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Paragraph 0032; 0033; 0063; 0067; 0068; 0070; 0073
(2017/09/02)
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- Synthetic quinolone signal analogues inhibiting the virulence factor elastase of Pseudomonas aeruginosa
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We explore the chemical space of Pseudomonas quinolone signal analogs as privileged structures and report the discovery of a thioquinolone as a potent inhibitor of the important virulence factor elastase of the human pathogen Pseudomonas aeruginosa. We provide evidence that the derivative binds to the active site zinc of elastase and additionally acts as a fluorescent zinc sensor.
- Szamosvári, Dávid,Reichle, Valentin F.,Jureschi, Monica,B?ttcher, Thomas
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supporting information
p. 13440 - 13443
(2016/11/19)
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- Copper(II)-Catalyzed Single-Step Synthesis of Aryl Thiols from Aryl Halides and 1,2-Ethanedithiol
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A highly efficient transition metal-catalyzed single-step synthesis of aryl thiols from aryl halides has been developed employing copper(II) catalyst and 1,2-ethanedithiol. The key features are use of readily available reagents, a simple operation, and relatively mild reaction conditions. This new protocol shows a broad substrate scope with excellent functional group compatibility. A variety of aryl thiols are directly prepared from aryl halides in high yields. Furthermore, the aryl thiols are used in situ for the synthesis of more advanced molecules such as diaryl sulfides and benzothiophenes.
- Liu, Yajun,Kim, Jihye,Seo, Heesun,Park, Sunghyouk,Chae, Junghyun
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supporting information
p. 2205 - 2212
(2015/07/27)
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- TMSI-Promoted vinylogous michael addition of siloxyfuran to 2-substituted chromones: A general approach for the total synthesis of chromanone lactone natural products
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A concise and facile synthetic protocol for the construction of the 2-γ-lactone chromanone skeleton has been achieved through a TMSI-promoted diastereoselective vinylogous Michael addition of siloxyfuran to 2-substituted chromones. The applicability of this method is demonstrated through the rapid access to the total syntheses of (±)-microdiplodiasone, (±)-lachnone C, and (±)-gonytolides C and G.
- Liu, Jie,Li, Zhanchao,Tong, Pei,Xie, Zhixiang,Zhang, Yuan,Li, Ying
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supporting information
p. 1632 - 1643
(2015/02/19)
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- CHROMAN - SPIROCYCLIC PIPERIDINE AMIDES AS MODULATORS OF ION CHANNELS
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The invention relates to chroman spirocyclic piperidine amide derivatives useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
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Page/Page column 75-76
(2012/09/10)
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- Substituted 2-(3′,4′,5′-trimethoxybenzoyl)-benzo[b] thiophene derivatives as potent tubulin polymerization inhibitors
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The central role of microtubules in cell division and mitosis makes them a particularly important target for anticancer agents. On our early publication, we found that a series of 2-(3′,4′,5′-trimethoxybenzoyl)-3- aminobenzo[b]thiophenes exhibited strong antiproliferative activity in the submicromolar range and significantly arrested cells in the G2-M phase of the cell cycle and induced apoptosis. In order to investigate the importance of the amino group at the 3-position of the benzo[b]thiophene skeleton, the corresponding 3-unsubstituted and methyl derivatives were prepared. A novel series of inhibitors of tubulin polymerization, based on the 2-(3,4,5-trimethoxybenzoyl)-benzo[b]thiophene molecular skeleton with a methoxy substituent at the C-4, C-5, C-6 or C-7 position on the benzene ring, was evaluated for antiproliferative activity against a panel of five cancer cell lines, for inhibition of tubulin polymerization and for cell cycle effects. Replacing the methyl group at the C-3 position resulted in increased activity compared with the corresponding 3-unsubstituted counterpart. The structure-activity relationship established that the best activities were obtained with the methoxy group placed at the C-4, C-6 or C-7 position. Most of these compounds exhibited good growth inhibition activity and arrest K562 cells in the G2-M phase via microtubule depolymerization.
- Romagnoli, Romeo,Baraldi, Pier Giovanni,Carrion, Maria Dora,Cruz-Lopez, Olga,Tolomeo, Manlio,Grimaudo, Stefania,Cristina, Antonietta Di,Pipitone, Maria Rosaria,Balzarini, Jan,Brancale, Andrea,Hamel, Ernest
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experimental part
p. 5114 - 5122
(2010/09/14)
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- COUMARIN-BASED COMPOUNDS
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Compounds including those of the Formula I where X, R1, R2 and subscript t are as defined herein, useful as γ-secretase inhibitors, are provided, as are compositions comprising the compounds, as well as methods for use of the compoun
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Page/Page column 134
(2010/07/09)
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- Facile preparation of 3-substituted benzisothiazoles from o-mercaptoacylphenones
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(Chemical Equetion Presentation) A synthesis of 3-substituted benzisothiazoles starting from readily available o-mercaptoacylphenones is presented. The key cyclization step features a mild S-nitrosation and its succeeding intramolecular aza-Wittig reactio
- Devarie-Baez, Nelmi O.,Xian, Ming
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scheme or table
p. 752 - 754
(2010/04/05)
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- NOVEL PYRROLE DERIVATIVE HAVING UREIDE GROUP AND AMINOCARBONYL GROUP AS SUBSTITUENTS
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Objects of the present invention are to study on the synthesis of a novel pyrrole derivative having a ureido group and an aminocarbonyl group as substituents or a salt thereof, to find a pharmacological effect of the derivative or a salt thereof, and to f
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Page/Page column 34
(2009/12/05)
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- OPHTHALMIC COMPOSITIONS FOR TREATING OCULAR HYPERTENSION
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This invention relates to potent potassium channel blocker compounds of Formula I or a formulation thereof for the treatment of glaucoma and other conditions which leads to elevated intraoccular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.
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Page/Page column 42
(2008/06/13)
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- The Selective Deprotection of Thioesters Using Titanium(IV) Chloride/Zinc
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A new method for deprotection of thioesters using TiCl4/Zn at 0-25 deg C is described. The procedure chemoselectively cleaves the S-CO bond in thioesters in the presence of other carbonyl functional groups and other protecting groups to cleanly produce thiols.
- Jin, Chung Keun,Jeong, Hyung Jae,Kim, Min Kyu,Kim, Ju Young,Yoon, Yong-Jin,Lee, Sang-Gyeong
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p. 1956 - 1958
(2007/10/03)
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- Electrophilic Reactions of Carbenoids. Synthesis of Fused Heterocyclic Systems via Intramolecular Nucleophilic Substitution of Carbenoids
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Intramolecular nucleophilic substitution of carbenoids with oxygen, nitrogen, and sulfur nucleophiles leading to the synthesis of fused heterocyclic compounds has been studied.For the purpose of this investigation styryl type gem-dihalides 4, 8, 18, 20, 28 containing a nucleophilic substituent in the ortho position of the aromatic ring have been synthesized.Carbenoids have been generated in those systems by the halogen - metal exchange reaction and shown to readily undergo intramolecular nucleophilic substitution by the properly located nucleophilic group (OH, SH, or NH2).As a result a new synthetic route to benzofurans, thianaphthenes, and indoles has been established based on nucleophilic substitution of vinyl halides by an ortho substituent.The dramatic increase of reactivity of vinyl halides upon introduction of lithium has been explained as being due to metal-assisted ionization.
- Topolski, Marek
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p. 5588 - 5594
(2007/10/03)
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- ETUDE DES REACTIONS DE SRN1-PARTIE 10 ACTION DE SULFANIONS SUR LES HALOGENURES D'ARYLE FONCTIONNALISES. SYNTHESE DIRECTE DE BENZOTHIOPHENES ET THIENOPYRIDINES
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Functionalized aromatic halides Ar1XY (Ar1=C6H4, Y=OCH3,CONH2,CN,COCH3,CHO,COC6H5) undergo SRN1 reactions with sulphur anions -SR, either simple (R=C2H5,CH2C6H5) or functionalized (R=(CH2)2OH,(CH2)2CO2Et,CH2CO2Et).Products Ar1YS- formed from the fragmentation of the radical anion Ar1YSR- are related to the redox potential of the aryl moiety Ar1Y and with the energy of the bond S-R.In the heterocyclic series (Ar2=pyridine, Ar3=quinoline) a similar relationship appears but a competitive SN(AR) reaction occurs for pyridine substrates bearing an electron withdrawing group.A direct synthesis of benzothiophen via SRN1 reaction and an improved synthesis of thienopyridines based on the SN(Ar) reaction are reported.
- Beugelmans, Rene,Bois-Choussy, Michele,Boudet, Bernard
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p. 4153 - 4162
(2007/10/02)
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- NEW SYNTHETIC METHODS : SODIUM ALKANECHALCOGENATES AS DEMETHYLATING AGENTS. SCOPE, LIMITATION AND NEW ONE-POT SYNTHESIS OF DIARYLDISELENIDES.
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Sodium alkanechalcogenates (S, Se) cleave the alkylarylchalcogenides (O, S, Se).The versatility of such reagents is developed and applied to a new synthesis of diaryldiselenides.
- Evers, Michel,Christiaens, Leon
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p. 377 - 380
(2007/10/02)
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- ON THE SYNTHESIS OF 2-METHYLCHROMENE-4-THIONE AND 2-METHYL-1-THIOCHROMONE
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Routes to 2-methylchromene-4-thione and 2-methyl-1-thiochromone from β-ketophenol sources are reported.
- Coombes, Richard C.,Fenton, David E.
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p. 139 - 142
(2007/10/02)
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