Stereochemistry Balances Cell Permeability and Solubility in the Naturally Derived Phepropeptin Cyclic Peptides

Cyclic peptide (CP) natural products
provide useful model systems
for mapping “beyond-Rule-of-5” (bRo5) space. We identified
the phepropeptins as natural product CPs with potential cell permeability.
Synthesis of the phepropeptins and epimeric analogues revealed much
more rapid cellular permeability for the natural stereochemical pattern.
Despite being more cell permeable, the natural compounds exhibited
similar aqueous solubility as the corresponding epimers, a phenomenon
explained by solvent-dependent conformational flexibility among the
natural compounds. When analyzing the polarity of the solution structures
we found that neither the number of hydrogen bonds nor the total polar
surface area accurately represents the solvation energies of the high
and low dielectric conformations. This work adds to a growing number
of natural CPs whose solvent-dependent conformational behavior allows
for a balance between aqueous solubility and cell permeability, highlighting
structural flexibility as an important consideration in the design
of molecules in bRo5 chemical space.