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

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