Studies on Griseolic Acid Derivatives. VII. Synthesis and Phosphodiesterase Inhibitory Activity of the C^4'-C^5' Hydrogenated Products of Griseolic Acid and Their Base-Exchanged Derivatives

Abstract

Addition reactions of the C^4'-C^5' double bond of griseolic acid were investigated. C⁴'-C⁵' Dihydrogriseolic acid was obtained by reduction of the adduct having halogen at the 4^'-position. The ring juncture of the two five-membered rings of the C^4'-C^5' dihydro derivatives was of all- “cis” configuration. Acetolysis of the protected dihydrogriseolic acid gave the corresponding 1'-acetoxy sugar derivative. Reaction of this sugar derivative with silylated bases gave guanine and uracil derivatives of the dihydrogriseolic acid. The cyclic nucleotide phosphodiesterase (PDE)-inhibitory activity of the C^4'-C^5' cis dihydrogriseolic acid derivative was weaker than that of griseolic acid. The uracil derivative of C^4'-C^5' cis dihydrogriseolic acid completely lost the inhibitory activity against both adenosine 3^', 5^'-cyclic monophosphate (cAMP) and guanosine ^3', ^5'-cyclic monophosphate (cGMP) PDE, whereas the guanine derivative showed reduced inhibitory activity against cAMP PDE, but retained its activity against cGMP PDE. It was also apparent that the C^4'-C^5' trans dihydro derivative which was obtained as a minor product from the same culture broth of griseolic acid had almost the same inhibitory activity as griseolic acid.