121425-19-2Relevant academic research and scientific papers
Design and discovery of 3-aryl-5-substituted-isoquinolin-1-ones as potent tankyrase inhibitors
Elliott, Richard J. R.,Jarvis, Ashley,Rajasekaran, Mohan B.,Menon, Malini,Bowers, Leandra,Boffey, Ray,Bayford, Melanie,Firth-Clark, Stuart,Key, Rebekah,Aqil, Rehan,Kirton, Stewart B.,Niculescu-Duvaz, Dan,Fish, Laura,Lopes, Filipa,McLeary, Robert,Trindade, Ines,Vendrell, Elisenda,Munkonge, Felix,Porter, Rod,Perrior, Trevor,Springer, Caroline,Oliver, Antony W.,Pearl, Laurence H.,Ashworth, Alan,Lord, Christopher J.
supporting information, p. 1687 - 1692 (2015/09/21)
The tankyrase proteins (TNKS, TNKS2), members of the PARP superfamily of enzymes, are attractive anti-cancer drug targets, particularly as inhibition of their catalytic activity has been shown to antagonise oncogenic WNT signalling. To identify chemical inhibitors of tankyrase we carried out an in silico small molecule screen using a set of 'PARP-binding' pharmacophores together with a generated (liganded) tankyrase homology model. This approach identified a structurally diverse set of ～1000 compounds for further study. Subsequent in vitro screening of recombinant tankyrase protein identified a subset of 59 confirmed inhibitors. Early optimisation followed by cell-based studies in WNT-dependent tumour cells, as well as co-crystallisation studies, identified a novel class of 3-aryl-5-substituted isoquinolin-1-ones, such as 21, that exhibit potent inhibition of tankyrase activity as well as growth inhibition of colorectal cancer cells.
3-ARYL-5-SUBSTITUTED-ISOQUINOLIN-1-ONE COMPOUNDS AND THEIR THERAPEUTIC USE
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Paragraph 1278-1282, (2015/04/15)
The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 3-aryl-5-substituted-2H-isoquinolin-1-one compounds that, inter alia, inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.
A practical in situ generation of the schwartz reagent. reduction of tertiary amides to aldehydes and hydrozirconation
Zhao, Yigang,Snieckus, Victor
supporting information, p. 390 - 393 (2014/04/03)
A new, highly efficient in situ protocol (Cp2ZrCl2/LiAlH(OBu-t)3) is described for the generation of the Schwartz reagent which provides a convenient method for the amide to aldehyde reduction and the regioselective hydrozirconation-iodination of alkynes and alkenes. Highlighted are chemoselective reductions of benzamides derived by directed ortho metalation (DoM) chemistry, allowing the synthesis of valuable 1,2,3-substituted benzaldehydes. The single-step, three-component process proceeds in a very short reaction time, shows excellent functional group compatibility, and uses inexpensive and long-storage stable reducing reagents.
Directed Ortho Metalation of N,N-Diethylbenzamides. Silicon Protection of Ortho Sites and the o-Methyl Group
Mills, Robert J.,Taylor, Nicholas J.,Snieckus, Victor
, p. 4372 - 4385 (2007/10/02)
New general methodology of value in aromatic chemistry based on silicon protection of preferred ortho metalation sites in benzamides and o-methyl groups in o-toluamides (1, 2, Scheme I) is described.According to these methodologies, routes (Scheme II and V) to 1,2,5-, 1,2,4,5-, and 1,2,3-substituted aromatics with a variety of functionalities and oxidation states have been developed (Tables I and II).These tactics are used for the synthesis of difficult to access halo (10a-b, Scheme III) and methyl (21,25, Scheme VI) heterocycles.Ipso bromodesilylation reactions with bromine lead regiospecifically to o-bromobenzamides (12a,c, 14, Scheme IV).Walk-around-the-ring metalation processes provide highly substituted aromatics 27, 28, 29, and 30 (Scheme VII); the X-ray structure of the hexasubstituted derivative 30 shows a significant puckering of the aromatic ring.Cesium fluoride induced carbodesilylation of o-silylbenzamides with benzaldehyde affords, after TsOH cyclization, phthalides (31a-c, Scheme VIII) and constitutes a neutral alternative to the directed ortho metalation approach. α- and α,α-silylated o-toluamides are used in fluoride-mediated carbodesilylation (34a,d, Scheme IX) and desilylative Peterson olefination (35, Scheme X) procedures, respectively.The utility of α-silylated o-toluamide for the synthesis of a tetralin (38, Scheme XI) via an o-quinodimethane species is given.
