Merging Natural Product Structures with Pharmaceutical Leads: Unnatural Enantiomers of Estranes as Glucocorticoid Receptor Modulators That Suppress TNF‑α and IL‑6 Release

Natural products are widely recognized as valuable starting
points
for the development of therapeutics, with synthetic tetracyclic triterpenoids
(e.g., steroids) being the most well represented among the drugs approved
by the Food and Drug Administration. Here, recently developed synthetic
tools for concise, asymmetric, and convergent construction of steroidal
systems are leveraged to drive a program aimed at identifying novel
glucocorticoid receptor (GR) modulators. While glucocorticoids have
been extensively used as anti-inflammatory agents, they are plagued
by severe side effects that include bone loss, muscle wasting, and
metabolic disease. Ultimately, a program targeting the unnatural enantiomers
of estranes (ent-estranes) that are practically inaccessible
from natural product derivatization (semisynthesis) has resulted in
the identification of a new class of potent dissociated GR modulators.
We identify several leads with >99% efficacy as antagonists of
GR
trans-activation (potency within 10-fold of that of mifepristone)
and further characterize examples that also inhibit release of pro-inflammatory
cytokines IL-6 and TNF-α.