- Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide N-Methyltransferase
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Nicotinamide N-methyltransferase (NNMT) catalyzes the methyl transfer from the cofactor S-adenosylmethionine to nicotinamide and other pyridine-containing compounds. NNMT is an important regulator for nicotinamide metabolism and methylation potential. Aberrant expression levels of NNMT have been implicated in cancer, metabolic, and neurodegenerative diseases, which makes NNMT a potential therapeutic target. Therefore, potent and selective NNMT inhibitors can serve as valuable tools to investigate the roles of NNMT in its mediated diseases. Here, we applied a rational strategy to design and synthesize the tight-binding bisubstrate inhibitor LL320 through a novel propargyl linker. LL320 demonstrates a Ki value of 1.6 ± 0.3 nM, which is the most potent inhibitor to date. The cocrystal structure of LL320 confirms its interaction with both the substrate and cofactor binding sites on NNMT. Importantly, this is the first example of using the propargyl linker to construct potent methyltransferase inhibitors, which will expand our understanding of the transition state of methyl transfer.
- Chen, Dongxing,Li, Linjie,Diaz, Krystal,Iyamu, Iredia D.,Yadav, Ravi,Noinaj, Nicholas,Huang, Rong
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p. 10783 - 10797
(2019/12/25)
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- Chemo- and Regioselective Organo-Photoredox Catalyzed Hydroformylation of Styrenes via a Radical Pathway
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An unprecedented, chemo- and regioselective, organo-photoredox catalyzed hydroformylation reaction of aryl olefins with diethoxyacetic acid as the formylation reagent is described. In contrast to traditional transition metal promoted ionic hydroformylation reactions, the new process follows a unique photoredox promoted, free radical pathway. In this process, a formyl radical equivalent, produced from diethoxacetic acid through a dye (4CzIPN) photocatalyzed, sequential oxidation-decarboxylation route, regio- and chemoselectively adds to a styrene substrate. Importantly, under the optimized reaction conditions the benzylic radical formed in this manner is reduced by SET from the anion radical of 4CzIPN to generate a benzylic anion. Finally, protonation produces the hydroformylation product. By using the new protocol, aldehydes can be generated regioselectively in up to 90% yield. A broad array of functional groups is tolerated in the process, which takes place under mild, metal-free conditions.
- Huang, He,Yu, Chenguang,Zhang, Yueteng,Zhang, Yongqiang,Mariano, Patrick S.,Wang, Wei
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supporting information
p. 9799 - 9802
(2017/08/02)
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- COMPOUNDS AND METHODS for the inhibition of HDAC
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Disclosed are compounds having the formula: wherein X1, X2, X3, R1, R2, R3, R4, Y, A, Z, L and n are as defined herein, and methods of making and using the same.
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Paragraph 0698-0699
(2015/11/24)
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- Double arylation of allyl alcohol via a one-pot heck arylation- isomerization-acylation cascade
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A one-pot, two-step catalytic protocol has been developed. A regioselective Heck coupling between aryl bromides and allyl alcohol leads to the generation of arylated allyl alcohols that in situ isomerize to give aldehydes, which then undergo an acylation reaction with a second aryl bromide. A variety of aryl bromides can be employed in both the initial Heck reaction and the acylation, providing easy access to a wide variety of substituted dihydrochalcones.
- Colbon, Paul,Ruan, Jiwu,Purdie, Mark,Mulholland, Keith,Xiao, Jianliang
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supporting information; experimental part
p. 5456 - 5459
(2011/12/05)
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- 7-PHENYL-ISOQUINOLINE-5-SULFONYLAMINO DERIVATIVES AS INHIBITORS OF AKT (PROTEINKINASE B)
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The present invention relates to compounds Formula (I) as inhibitors of AKT activity, which are useful for the treatment of susceptible neoplasms and viral infections.
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Page/Page column 28
(2010/02/12)
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- Organic compounds and their pharmaceutical use
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There are provided anti-allergic pharmaceutical compounds of formula: STR1 in which n is 0, 1 or 2; R1 is a hydrocarbyl group containing 6 to 30 carbon atoms and optionally substituted with an optionally substituted phenyl group; R2
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