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Synfacts 2015; 11(1): 0002
DOI: 10.1055/s-0034-1379642
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of GSK1324726A

Contributor(s):
Philip Kocienski
Bamborough P, * Prinjha RK. * et al. GlaxoSmithKline R&D, Villebon-sur-Yvette, France and Stevenage, UK
The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor.

J. Med. Chem. 2014;
57: 8111-8131
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Further Information

Publication History

Publication Date:
15 December 2014 (online)

 
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Key words

GSK1324726A - BET bromodomain inhibitors - asymmetric aza-Michael reaction - diastereoselective immonium ion cyclization - tetrahydro-isoquinolines

Significance

The BET family of bromodomain-containing proteins regulates expression of multiple genes including those involved in tumor cell growth and inflammation. GSK132476A is a BET bromodomain inhibitor that displays significant antiproliferative and anti-inflammatory effects.


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Comment

Key steps in the synthesis depicted are (1) the Pd-catalyzed asymmetric aza–Michael addition of 4-bromoaniline to (E)-isopropyl but-2-enoyl-carbamate (A) and (2) a diastereoselective cyclization of an immonium ion generated by reduction of C to generate the tetrahydroisoquinoline D.


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