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Configurational Stability of Bisindolylmaleimide Cyclophanes: From Conformers to the First Configurationally Stable, Atropisomeric Bisindolylmaleimides
Author(s) -
Barrett Simon,
Bartlett Stephen,
Bolt Amanda,
Ironmonger Alan,
Joce Catherine,
Nelson Adam,
Woodhall Thomas
Publication year - 2005
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200500520
Subject(s) - chemistry , steric effects , conformational isomerism , diastereomer , ring (chemistry) , stereochemistry , bisindolylmaleimide , crystallography , organic chemistry , protein kinase c , molecule , enzyme
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.