Configurational stability of bisindolylmaleimide cyclophanes: from conformers to the first configurationally stable, atropisomeric bisindolylmaleimides.
The bisindolylmaleimides are selective protein kinase inhibitors that can adopt two limiting diastereomeric (syn and anti) conformations. The configurational stability of a range of substituted and macrocyclic bisindolylmaleimides was investigated by using appropriate techniques. With unconstrained bisindolylmaleimides, the size of the 2-indolyl substituents was found to affect configurational stability, though not sufficiently to allow atropisomeric bisindolylmaleimides to be obtained. However, with a tether between the two indole nitrogen atoms in place, the steric effect of 2-indolyl substituents was greatly exaggerated, leading to large differences in configurational stability. The rate of interconversion of the syn and anti conformers varied by over twenty orders of magnitude through substitution of a bisindolylmaleimide ring system, which was constrained within a macrocyclic ring. Indeed, the first examples of configurationally stable atropisomeric bisindolylmaleimides are reported; the half-life for epimerisation of these compounds at room temperature was estimated to be >10(7) years.
Barrett
Simon
S
School of Chemistry, University of Leeds, UK.
Bartlett
Stephen
S
Bolt
Amanda
A
Ironmonger
Alan
A
Joce
Catherine
C
Nelson
Adam
A
Woodhall
Thomas
T
D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D006571:Heterocyclic Compounds / Q000737:chemistry*; D007202:Indicators and Reagents; D007211:Indoles / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008301:Maleimides / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D013696:Temperature
D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D007211:Indoles; D008301:Maleimides; C088060:bisindolylmaleimide