SYNTHESIS AND BIOLOGICAL-ACTIVITIES OF NEW CONFORMATIONALLY RESTRICTED ANALOGS OF (-)-INDOLACTAM-V - ELUCIDATION OF THE BIOLOGICALLY-ACTIVECONFORMATION OF THE TUMOR-PROMOTING TELEOCIDINS

The tumor-promoting teleocidins and their core structure (-)-indolacta m-V (1) exist in two stable conformers in solution at room temperature . The cis amide assumes a twist conformation while the trans amide exi sts in a sofa form. In order to identify the biologically active confo rmation of the teleocidins, we have synthesized new twist-restricted a nalogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N-13-de smethyl-N-13-allylindolactam-V (3) and a sofa-restricted analogue, (-) -5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-p romoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of He La cells. These three biological activities correlated well for each d erivative, Twist-restricted analogues 5a and 6 showed significant acti vities in the three assays, comparable to 1 itself. In contrast, sofa- restricted 22 showed little activity related to tumor promotion. Intro duction of a prenyl group into position 7 or 18 of 5a and 6 significan tly enhanced the activity while sofa-restricted (-)-5-prenylindolactam -V (23) showed only very weak activity. These results indicate that th e active conformation of the teleocidins and 1 is close to the twist f orm. This is the first evidence beating on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study al so describes the synthesis of hew biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a furth er application of the aza-Claisen rearrangement. Bridge formation betw een positions 5 and 13 of indolactam derivatives represents a particul arly effective analogue design strategy, allowing for the remote contr ol of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the developmen t of new protein kinase C activators with high isozyme selectivity.