Bufadienolide Antagonist of the Interleukin 6 Receptor (IL-6R)

Interleukin 6 (IL-6) is a pro-inflammatory cytokine that is secreted by T cells and macrophages to engender an immune response leading to inflammation. For example, IL-6 is a mediator of fever. This cytokine can cross the blood brain barrier to initiate the synthesis of prostoglandin E2 (shown above) in the hypothalamus, which modulates the body’s temperature setpoint. For this reason and others, a nonpeptide small-molecule antagonist for the interleukin 6 receptor is considered pharmacologically desirable.  The laboratory of Kenner Rice at NIH has developed an efficient process for the semisynthetic preparation of just such an antogonist. They have synthesized epoxyresibufogenin-3-formate from commercially available resibufogenin in just two steps. The authors have, for the first time, definitively characterized the stereochemical  configuration of the final product and shown that it acts as an IL-6 antagonist with high affinity. The critical  transformation of the synthetic sequence involves a robust and diastereoselective  epoxidation of resibufogenin-3-formate using in situ-generated methyl(trifluoromethyl)dioxirane (TFDO), as depicted in the scheme above. The protocol developed by the Rice laboratory was utilized to prepare hundreds of milligrams of this biomedically-relevant bufadienolide derivative.