Synthesis and pharmacological properties of new tetracyclic forskolin analogues

Abstract

New tetracyclic analogues of forskolin have been prepared by derivatization of the natural product. Treatment of a forskolin-derived cyclic thionocarbonate with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine resulted in the formation of a seven-membered cyclic carbonate derivative by an unprecedented rearrangement of an intermediate dialkoxycarbene or 1,3-dipole, whereas radical deoxygenation was followed by intramolecular cyclization with the double bond to form a third analogue. Two of the new analogues were investigated for their ability to activate adenylyl cyclases 1, 2 and 5. The introduction of another ring into the forskolin skeleton did not lead to a loss of binding affinity to the enzyme. Although the new compounds are much more spacious than forskolin, they still seem to fit into the binding pocket and were found to be partial agonists.