Abstract
In the course of our microbial screening studies to find novel nonsteroidal PR ligands, the fungal metabolites PF 1092 A, B and C were isolated from extracts of cell cultures of the rare fungus Penicillium oblatum PF 1092. We initially sought to identify the minimal pharmacophore by totally synthetic methods, and then clarified the structure-activity relationships (SAR) of PF 1092 (tetrahydronaphthofuranone) derivatives. SAR studies revealed that substituents at the 6-and 7-positions were critical for PR binding affinity and for agonist or antagonist activity. Furthermore, we synthesized tetrahydrobenzindolones possessing a lactam ring, which are chemically more stable than tetrahydronaphthofuranones and generally showed higher PR binding affinity than the corresponding tetrahydronaphthofuranones. The effects of representative antagonists, 37d and 49f, and representative agonists, 51c and 53a were confirmed in in vivo tests. In this report, we mainly describe the synthesis and SAR of these derivatives, as new nonsteroidal PR ligands.
