Configurational Stability of Bisindolylmaleimide Cyclophanes:From Conformers to the First Configurationally Stable,Atropisomeric Bisindolylmaleimides

摘要

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.