Indolocarbazoles.3. Synthesis of novel aza analogs of staurosporine and K 252a as PKC inhibitors.

Abstract

Indolocarbazole 4 and arcyriaflavin A 19 reacted under basic conditions with 1-benzyl-2,6-bis (benzotriazolyl)-piperidine to give 5 and 20. As an extension of this methodology other related bis benzotriazole derivatives were synthesized and coupled with 19 to obtain a variety of aza derivatives 3. N-debenzylation of these compounds gave novel PKC inhibitors.The vital and complex role played by the protein kinase C (PKC) isozymes in cellular processes continues to focus interest on inhibitors of these kinases, and their potential therapeutic applications.1 The diverse family of indolocarbazole natural products2 has provided staurosporine 1 and K-252a 2 as potent inhibitors of PKC; our own studies related to these compounds have resulted in a convenient route to highly potent analogs of 2,3 and uncovered an unusual skeletal rearrangement in the carbohydrate portion.4 In this paper, we describe the synthesis and properties of hitherto unknown aza analogs 3 of the natural products.