- Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3)
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PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive structure-activity relationship studies that target the allosteric binding site of PRMT3. We conducted design, synthesis, and evaluation of novel compounds in biochemical, selectivity, and cellular assays that culminated in the discovery of 4 and other highly potent (IC50 values: ～10-36 nM), selective, and cell-active allosteric inhibitors of PRMT3 (compounds 29, 30, 36, and 37). In addition, we generated compounds that are very close analogs of these potent inhibitors but displayed drastically reduced potency as negative controls (compounds 49-51). These inhibitors and negative controls are valuable chemical tools for the biomedical community to further investigate biological functions and disease associations of PRMT3.
- Kaniskan, H. ümit,Eram, Mohammad S.,Zhao, Kehao,Szewczyk, Magdalena M.,Yang, Xiaobao,Schmidt, Keith,Luo, Xiao,Xiao, Sean,Dai, Miao,He, Feng,Zang, Irene,Lin, Ying,Li, Fengling,Dobrovetsky, Elena,Smil, David,Min, Sun-Joon,Lin-Jones, Jennifer,Schapira, Matthieu,Atadja, Peter,Li, En,Barsyte-Lovejoy, Dalia,Arrowsmith, Cheryl H.,Brown, Peter J.,Liu, Feng,Yu, Zhengtian,Vedadi, Masoud,Jin, Jian
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p. 1204 - 1217
(2018/02/17)
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- An expedient synthesis of novel 2-substituted thiazolo[4,5-f]isoquinolines/ quinolines and benzo[1,2-d:4,3-d']bisthiazoles and their potential as inhibitors of COX-1 and COX-2
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An efficient, general synthesis of 2-substituted thiazolo[4,5-f] isoquinolines, thiazolo[4,5-f]-quinolines and benzo[1,2-d:4,3-d']bisthiazoles has been accomplished from 5-nitroisoquinoline/quinoline and 6-nitrobenzothiazole, respectively, and all the products have been thoroughly identified spectroscopically (IR, 1H and 13C NMR, LR/HR EI/FAB/ESI-MS). The synthesis of thiazolo[4,5-f]isoquinolines constitutes the first synthesis of this class of heteroarenes. Eighteen compounds, covering all three types, were screened for inhibition of COX-1 and COX-2, and some of them showed moderate activities. ARKAT-USA, Inc.
- Chakrabarty, Manas,Mukherji, Ajanta,Karmakar, Sulakshana,Mukherjee, Ratna,Nagai, Kenichiro,Geronikaki, Athina,Elenic, Pitta
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experimental part
p. 265 - 290
(2011/02/24)
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- A facile construction of the benz[c,d]indole framework
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The Bradsher cycloaddition of isoquinolinium salts has been applied to 5-acetaminoisoquinoline. In 3 simple steps: (i) quaternization of isoquinoline N (ii) cycloaddition with electron-rich dienophile (iii) dehydration, the benz[c,d]-indole framework is f
- Soll, Clifford E.,Franck, Richard W.
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p. 531 - 540
(2008/02/02)
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- Identification of novel and potent isoquinoline aminooxazole-based IMPDH inhibitors
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Screening of our in-house compound collection led to the discovery of 5-bromo-6-amino-2-isoquinoline 1 as a weak inhibitor of IMPDH. Subsequent optimization of 1 afforded a series of novel 2-isoquinolinoaminooxazole-based inhibitors, represented by 17, with single-digit nanomolar potency against the enzyme.
- Chen, Ping,Norris, Derek,Haslow, Kristin D.,Dhar, T. G. Murali,Pitts, William J.,Watterson, Scott H.,Cheney, Daniel L.,Bassolino, Donna A.,Fleener, Catherine A.,Rouleau, Katherine A.,Hollenbaugh, Diane L.,Townsend, Robert M.,Barrish, Joel C.,Iwanowicz, Edwin J.
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p. 1345 - 1348
(2007/10/03)
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- Antiparasitic agents: Part XV - Synthesis of 2-substituted 1(3)H-imidazoisoquinolines as anthelmintic agents
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5-(2,4-Dioxo-1H-quinazolin-3-yl)isoquinoline (14) and 2-(methyl-/carbomethoxyamino-/furyl-/trifluoromethyl)-1(3)H-imidazoisoquinolines (17, 20-22) have been synthesized and tested for their anthelmintic and antifilarial activities against Ancylosto
- Kumar, Pramod,Agarwal, Shiv K,Bhakuni, D S
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p. 177 - 182
(2007/10/02)
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