Synthesis, conformation and PKC isozyme surrogate binding of indolinelactam-Vs, new conformationally restricted analogues of (−)-indolactam-V

Abstract

New conformationally restricted analogues of tumor promoter (−)-indolactam-V ( 1 ), indolinelactam-Vs ( 8 , 11 ) and their hexyl derivatives at position 1 or 7 ( 9 , 10 , 12 , 13 ), were synthesized from 1 . (3 R)-Indolinelactam-V ( 8 ) adopted a conformation similar to the twist form of 1 with a cis amide, while the conformation of (3 S)-indolinelactam-V ( 11 ) was close to that of the sofa form of 1 with a trans amide. 7-Hexyl derivatives of 8 and 11 ( 10 , 13 ) showed binding affinities for C1 domains of protein kinase C (PKC) isozymes compared to 1 , but exhibited little selectivity among these PKC isozymes. However, introduction of the hexyl group at position 1 of 8 and 11 significantly enhanced their binding selectivity for novel PKC isozymes. The best selectivity for novel PKC isozymes was observed in (3 S)-1-hexylindolinelactam-V ( 12 ) with a sofa-like conformation. These results suggest that a sofa-restricted analogue of 1 with a hydrophobic chain at an appropriate position would be a promising lead for designing agents with a high selectivity for novel PKC isozymes.