- Discovery of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as novel and potent bromodomain and extra-terminal (BET) inhibitors with anticancer efficacy
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As epigenetic readers, bromodomain and extra-terminal domain (BET) family proteins bind to acetylated-lysine residues in histones and recruit protein complexes to promote transcription initiation and elongation. Inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for cancer. Herein, we describe our efforts toward the discovery of a novel series of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as BET inhibitors. Intensive structural modifications led to the identification of compound 35f as the most active inhibitor of BET BRD4 with selectivity against BET family proteins. Further biological studies revealed that compound 35f can arrest the cell cycle in G0/G1 phase and induce apoptosis via decreasing the expression of c-Myc and other proteins related to cell cycle and apoptosis. More importantly, compound 35f showed favorable pharmacokinetic properties and antitumor efficacy in MV4-11 mouse xenograft model with acceptable tolerability. These results indicated that BET inhibitors could be potentially used to treat hematologic malignancies and some solid tumors.
- Bian, Yuanyuan,Chen, Yadong,Hong, Qianqian,Jiang, Fei,Kong, Bo,Li, Hongmei,Lu, Tao,Ma, Yu,Ran, Ting,Tang, Weifang,Wang, Cong,Yang, Na,Zhang, Zhimin,Zheng, Wan,Zhu, Jiapeng,Zhu, Zhaohong
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- Rational design of fluorescent probes for targeted: In vivo nitroreductase visualization
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Nitroreductase (NTR) has been recognized as a biomarker for identifying the hypoxic status of cancers. Therefore, it is of high scientific interest to design effective fluorescent probes for tracking NTR activity. However, studies on elucidation of the structure-performance relationship of fluorescent probes and those providing valuable insight into optimized probe design have rarely been reported. Three BODIPY based fluorescent probes were made by conjugation of para-, ortho-, and meta-nitrobenzene to the BODIPY core via a thiolether bond, respectively. Our study revealed that the linkage and nitro substituent position significantly influence the capability of nitroreductase detection.
- Chen, Ji-An,Gao, Jie,Gu, Xianfeng,Li, Mimi,Tan, Jiahui,Yin, Xiaofan,Zhao, Zhen
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supporting information
p. 4744 - 4747
(2020/07/13)
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- Transition metal-free cyclization of N-boc-N-propargylenamines
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An efficient method for the synthesis of multi-substituted pyrroles was developed using basic cyclization of readily accessible N-Boc-N-propargylenamines. Despite the basic conditions, cleavage of the N-Boc group occurred easily. The process was rapid and afforded N-H-pyrroles with wide functional group tolerance in high yields.
- Chikayuki, Yuya,Higashiyama, Kimio,Ishikawa, Haruka,Kouno, Yasuaki,Sasaki, Shigeru,Teramoto, Hiroyoshi,Waki, Yoko,Yamauchi, Takayasu,Yonekawa, Shiori
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p. 719 - 746
(2020/07/13)
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- Synthesis and reactivity of 2-thionoester pyrroles: A route to 2-formyl pyrroles
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2-Functionalised pyrroles exhibit considerable synthetic utility. Herein, the synthesis and reactivity of 2-thionoester (-C(S)OR) pyrroles is reported. 2-Thionoester pyrroles were synthesised using a Knorr-type approach from aliphatic starting materials. 2-Thionoester pyrroles were reduced to the corresponding 2-formyl pyrroles, or the deuterated formyl variant, in one step using RANEY nickel, thereby removing the need for the much-utilised hydrolysis/decarboxylation/formylation steps that are typically required to convert Knorr-type 2-carboxylate pyrroles into 2-formyl pyrroles. 2-Thionoester pyrroles proved tolerant of typical functional group interconversions for which the parent 2-carboxylate pyrroles have become known.
- Kim, Min Joon,Gaube, Sophie M.,Beh, Michael H. R.,Smith, Craig D.,Thompson, Alison
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p. 31773 - 31780
(2019/10/19)
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- SPIROBODIPYs with spiropyran structure compound, preparation method and its use
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The invention discloses a SPIROBODIPYs compound with the spiropyrane structure. The compound has the following structural general formula (refer to the Specification), wherein R1, R2, R3 and R4 are alkyl substituents or aromatic substituents, R5 is an alkyl substituent, an alcohol hydroxyl substituent or a substituent with triple bonds at the tail end. The invention further discloses the application of the SPIROBODIPYs compound to a fluorescence molecular probe. The SPIROBODIPYs compound can be applied to controllable detection of physiological and pathological process of cells, and can be used for building living cell acid organelles or used as a novel fluorescent dye of a fluorescence molecular probe for detecting the acid environment of cancer cells.
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Paragraph 0020; 0057; 0059
(2016/11/02)
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- One-pot synthesis of asymmetric annulated bis(pyrrole)s
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Condensation of activated functionalized pyrroles with acetone results in asymmetric bis(pyrrole)s, formed via ring annulation. The methodology is somewhat general and can be applied to a variety of ketones, as well as to a range of pyrrolic substrates that do not bear electron-withdrawing groups directly adjacent to the pyrrole ring.
- Smithen, Deborah A.,Cameron, T. Stanley,Thompson, Alison
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supporting information; experimental part
p. 5846 - 5849
(2012/01/13)
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- Design and development of a new pyrromethene dye with improved photostability and lasing efficiency: Theoretical rationalization of photophysical and photochemical properties
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(Chemical Equation Presented) In an attempt to develop a photostable and efficient pyrromethene compound for use in liquid dye lasers, three congeners of the commercially available pyrromethene 567 (PM567) laser dye were synthesized and their photophysical properties, lasing efficiencies, and photochemical stabilities were studied. In general the presence of an aryl group at C-8 of the pyrromethene chromophore increased the photostability. One of the congeners possessing a C-8 trimethoxyphenyl moiety showed significantly improved lasing parameters than PM567. Compared to PM567, the photochemical stability of the new dye was 2-fold, while it showed an equivalent lasing efficiency to that of PM567 at a significantly lower concentration. The increased photostability of these new dye molecules could be explained by theoretical calculation on their capacity to generate singlet oxygen (1O2) and probability of reaction with 1O2. Our calculations were in agreement with the experimental results and indicated that a systematic design of new derivatives of pyrromethene chromophore might lead to improved laser dye molecules.
- Mula, Soumyaditya,Ray, Alok K.,Banerjee, Manas,Chaudhuri, Tandrima,Dasgupta, Kamalesh,Chattopadhyay, Subrata
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p. 2146 - 2154
(2008/09/19)
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- Versatility of Weinreb amides in the Knorr pyrrole synthesis
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N-Methoxy-N-methyl-α-enaminocarboxamides were prepared starting from enamines and Weinreb α-aminoamides. Their reaction with oganometallic compounds and subsequent cyclization constitute a versatile alternative in the Knorr pyrrole synthesis.
- Alberola, Angel,Ortega, Alfonso Gonzalez,Sadaba, M. Luisa,Sanudo, Carmen
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p. 6555 - 6566
(2007/10/03)
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- Aminosilanes in Organic Synthesis. Addition of Organocopper Reagents on γ-Bis(trimethylsilyl)amino-α-Acetylenic Amides, Esters and Ketones. Stereochemistry und Some Synthetic Uses
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The stereochemical outcome of the carbocupration of γ-bis(trimethylsilyl)amino-α-acetylenic amide, esters and ketone was studied.A judicious choice of substrate, reagent and(or) reaction conditions allows to perform highly stereoselective cis or trans addition.The intermediate vinylic copper adducts, with (E) or (Z) configuration, react with electrophilic reagents to provide short routes to substituted pyrrolinones and pyrroles.Keywords: Silylamines, propargylamines, organocopper regaents, stereochemistry, nitrogen heterocycles.
- Corriu, Robert J. P.,Bolin, Geng,Iqbal, Javed,Moreau, Joel J. E.,Vernhet, Claude
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p. 4603 - 4618
(2007/10/02)
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