SYNTHESIS, MOLECULAR MODELING, 2-D NMR, AND BIOLOGICAL EVALUATION OF ILV MIMICS AS POTENTIAL MODULATORS OF PROTEIN-KINASE-C

To study the structural determinants required for protein kinase C (PK C) activation by indolactam V (ILV) for purposes of arriving at simple r versions of this PKC activator, four simplified analogues of ILV (4a -c and 14a) were synthesized. These analogues contain a benzene ring i n place of the indole group of ILV and were designed for synthesis bec ause molecular modeling studies revealed these simplified structures t o possess readily accessible [ILV]-sofa-like conformations, thus mimic king the literature-reported bioactive conformation of ILV. During the course of designing these analogues, a more rigorous conformational s earch program (SysSearch) was developed to analyze the highly function alized nine-membered lactam ring system present in ILV. The results of the molecular modeling studies using the SysSearch program on which t he design of these analogues was based were confirmed by 2-D NMR and X -ray studies. The compounds of this series were constructed by use of the Mitsunobu reaction to generate the unique nine-membered lactam rin g present in these structures. Two routes to compound 4a are presented , one of which utilizes the amino acid building blocks, L-valine and L -phenylalanine, to fix the stereochemistry of its two asymmetric cente rs. The biological studies reveal that these new analogues fail to mod ulate PKC activity, and thus they exclude the possibility that a benze ne ring can serve as a surrogate of the indole ring of ILV. The presen t work therefore indicates that the nine-membered lactam ring moiety o f ILV in an [ILV]sofa conformation is not a sufficient structural dete rminant for PKC activation.