Design and synthesis of unprecedented 9-and 10-membered cyclonucleosides with PRMT5 inhibitory activity

Synthesis of medium-sized rings is known to be challenging due to high transannular strain especially for 9- and 10-membered rings. Herein we report design and synthesis of unprecedented 9- and 10-membered purine 8,5 ' cyclonucleosides as the first cyclonucleoside PRMT5 inhibitors. The cocrystal structure of PRMT5:MEP50 in complex with the synthesized 9-membered cyclonucleoside 1 revealed its binding mode in the SAM binding pocket of PRMT5.

Automated summary

The design and synthesis of unprecedented 9- and 10-membered purine 8,5' cyclonucleosides as the first cyclonucleoside PRMT5 inhibitors is reported. The cocrystal structure of PRMT5:MEP50 in complex with the synthesized 9-membered cyclonucleoside 1 revealed its binding mode in the SAM binding pocket of PRMT5.