Catalysis Enabled Synthesis of Tricyclic-PGDM Methyl Ester and Design of Potent PRMT5:MEP50 Inhibitors

A concise and scalable total synthesis of the therapeutically relevant methyl ester of the prostaglandin D₂ metabolite, tricyclic-PGDM, was accomplished in 8 steps from a known and easily accessed cyclopentene-diol derivative. The route features three key transition metal catalyzed steps. These steps include: a nickel catalyzed Ueno-Stork type dicarbofunctionalization which generates two consecutive stereocenters on the central cyclopentane core, a late-stage palladium-catalyzed carbonylative oxaspirolactonization, and a Z-selective cross metathesis to introduce the Z-butenoate side chain- a motif difficult to introduce through traditional protocols and which caused significant issues in the previous total syntheses of tricyclic-PGDM. Through this route, we have accumulated 75 mg of material for an ¹⁸O tricyclic-PGDM clinical assay which previously suffered from a material shortage. In addition to completing the synthesis, we generalized the Z-selective cross metathesis and nickel catalyzed Ueno-Stork protocols to numerous other substrates further demonstrating the utility of these transformations. 

Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups from the cofactor SAM to arginine residues on various cytosolic and nuclear proteins. Of the nine members of the PRMT family, PRMT5 has been the most extensively studied and has been shown to regulate processes such as the DNA damage response, cell proliferation, and mRNA translation. Although numerous pathways have been identified that regulate PRMT5 activity, the cytosolic protein MEP50 has been identified as a key regulator in many diseases. PRMT5 and MEP50 interact to form a hetero-octameric complex, which can modulate the activity of PRMT5 for many cellular processes. Two new generations of PRMT5:MEP50 inhibitors were strategically designed and synthesized, which do not suffer from chemical instability like our previously most potent analogues. Our best compounds have IC₅₀ values ranging from 512 to 2.5 nM in LNCaP cells, and were confirmed to target the PRMT5:MEP50 interaction through BiFC analysis.