- Synthesis and Evaluation of Dimeric Derivatives of Diacylglycerol-Lactones as Protein Kinase C Ligands
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Protein kinase C (PKC) mediates a central cellular signal transduction pathway involved in disorders such as cancer and Alzheimer's disease. PKC is regulated by binding of the second messenger sn-1,2-diacylglycerol (DAG) to its tandem C1 domains, designated C1a and C1b, leading both to PKC activation and to its translocation to the plasma membrane and to internal organelles. Depending on the isoform, there may be differences in the ligand selectivity of the C1a and C1b domains, and there is different spacing between the C1 domains of the conventional and novel PKCs. Bivalent ligands have the potential to exploit these differences between isoforms, yielding isoform selectivity. In the present study, we describe the synthesis of a series of dimeric derivatives of conformationally constrained diacylglycerol (DAG) analogs (DAG-lactones). We characterize the derivatives in vitro for their binding affinities, both to a single C1 domain (the C1b domain of PKCδ) as well as to the conventional PKCα isoform and the novel PKCδ isoform, and we measure their abilities to cause translocation of PKCδ and PKC? in intact cells. The dimeric compound with the 10-carbon linker was modestly more effective for the isolated PKCδ C1b domain than was the monomeric compound. For the intact PKCα and PKCδ, the shortest DAG-lactone dimer had similar affinity to the monomer and affinity decreased progressively up to the 16-carbon linker. The dimeric derivatives did not cause the Golgi accumulation of PKCδ. The present results provide important insights into the development of new chemical tools for biological studies on PKC.
- Ohashi, Nami,Kobayashi, Ryosuke,Nomura, Wataru,Kobayakawa, Takuya,Czikora, Agnes,Herold, Brienna K.,Lewin, Nancy E.,Blumberg, Peter M.,Tamamura, Hirokazu
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- A General and mild catalytic α-alkylation of unactivated esters using Alcohols
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Catalytic α-alkylation of esters with primary alcohols is a desirable process because it uses low-toxicity agents and generates water as the by-product. Reported herein is a NCP pincer/Ir catalyst which is highly efficient for α-alkylation of a broad scope of unactivated esters under mild reaction conditions. For the first time, alcohols alkylate unactivated α-substituted acyclic esters, lactones, and even methyl and ethyl acetates. This method can be applied to the synthesis of carboxylic acid derivatives with diverse structures and functional groups, some of which would be impossible to access by conventional enolate alkylations with alkyl halides. In a pinch: An NCP pincer/iridium catalyst is highly efficient for the α-alkylation of unactivated esters using alcohol under mild reaction conditions. The reaction is simple, clean, and scalable (1-10 mmol), and the scope with respect to the ester is wide.
- Guo, Le,Ma, Xiaochen,Fang, Huaquan,Jia, Xiangqing,Huang, Zheng
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supporting information
p. 4023 - 4027
(2015/03/30)
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- Nickel-catalyzed cross-coupling of unactivated alkyl halides and tosylate carrying a functional group with alkyl and phenyl Grignard reagents
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By the use of catalytic amounts of a nickel salt and a 1,3-butadiene, primary and secondary alkyl Grignard reagents undergo cross-coupling with alkyl bromides, iodide, and tosylate carrying a functional group such as amide, ester, and ketone at 0 °C in THF. The present procedure provides a simple, convenient, and practical method for construction of carbon chains in the presence of various functional groups. PhMgBr also gave the corresponding coupling product in a moderate yield.
- Singh, Surya Prakash,Terao, Jun,Kambe, Nobuaki
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scheme or table
p. 5644 - 5646
(2011/02/25)
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- A FACILE PROCEDURE FOR O-TRITYLATION
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The title operation is achieved via readily accessible organosilicon compounds.
- Murata, S.,Noyori, R.
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p. 2107 - 2108
(2007/10/02)
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- TRIMETHYLSILYL TRIFLATE IN ORGANIC SYNTHESIS
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Trimethylsilyl triflate is a powerful silylating agent for organic compounds and acts as a catalyst which accelerates a variety of nucleophilic reactions in aprotic media.The reactions proceed via one-center, electrophilic coordination of the silyl group to hetero functional groups and exhibit unique selectivities.
- Noyori, R.,Murata, S.,Suzuki, M.
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p. 3899 - 3910
(2007/10/02)
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- Chain extension with tert-butyl lithioacetate
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Iodides containing methylene-interrupted triple or double bonds can be chain-extended in 45-73percent yield by reaction with tert-butyl lithioacetate in THF/HMPT at -35 deg C and subsequent acid-catalyzed thermolysis at 100 deg C.Alkyl and allyl bromides or iodides give acids in yields of 60 to 89percent.In some cases, minor amounts of methyl ketones were found.Alkyl chlorides and alkyl methane-, benzene- or p-toluenesulphonates are not suitable.
- Bos, Wil,Pabon, Henk J. J.
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p. 141 - 142
(2007/10/02)
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