Synthesis, molecular modeling, 2-D NMR, and biological evaluation of ILV mimics as potential modulators of protein kinase C

Abstract

To study the structural determinants required for protein kinase C (PKC) activation by indolactam V (ILV) for purposes of arriving at simpler versions of this PKC activator, four simplified analogues of ILV , 2,5-benzodiazonin-4-one derivatives (4a-c and 14a), were synthesized. These analogues contain a benzene ring in place of the indole group of ILV and were designed for synthesis because molecular modeling studies revealed these simplified structures to possess readily accessible [ILV]-sofa-like conformations, thus mimicking the literature-reported bioactive conformation of ILV. During the course of designing these analogues, a more rigorous conformational search program (SysSearch) was developed to analyze the highly functionalized nine-membered lactam ring system present in ILV. The compounds of this series were constructed by use of the Mitsunobu reaction to generate the unique nine-membered lactam ring present in these structures. The biological studies reveal that these new analogues fail to modulate PKC activity, and thus they exclude the possibility that a benzene ring can serve as a surrogate of the indole ring of ILV