Exploiting the Biginelli reaction: nitrogen-rich pyrimidine-based tercyclic α-helix mimetics. Issue 9 (3rd March 2016)

• Record Type: Journal Article
• Authors: Lim, Zelong; Duggan, Peter J.; Wan, Soo San; Lessene, Guillaume; Meyer, Adam G.; Tuck, Kellie L.
• Is Part Of: Tetrahedron. Volume 72:Issue 9(2016)
• Page Start: 1151
• Page End: 1160
• Publication Date: 2016-03-03
• Subjects: Biginelli reaction -- Pyrimidine -- Alpha-helix mimetics -- Bcl-xL inhibitor; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2015.12.044
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: Several rationally designed pyrimidine-based scaffolds intended to mimic the spatial projection of the i, i +3, and i +7 residues of an α-helix and also possess improved aqueous solubility were prepared. A Biginelli-oxidation process was used to form the central pyrimidine ring of these scaffolds, which was subsequently manipulated to form pyrimidine-based tercyclic α-helix mimetics. A pyrimidine-based scaffold designed to mimic the α-helical BH3 domain of the pro-apoptotic Bak protein was also prepared as a putative inhibitor of the Bcl-xL /Bak protein-protein interaction. The pyrimidine-based tercyclic α-helix mimetics, and the putative Bcl-xL inhibitor, were assessed using a luminescence competition assay, however, none displayed inhibitory activity against Bcl-xL or Mcl-1. Graphical abstract: