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ACS Med Chem Lett. 2016 Jun 6;7(8):757-61. doi: 10.1021/acsmedchemlett.6b00100. eCollection 2016 Aug 11.

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

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Chemistry and Biochemistry, University of California Santa Cruz , Santa Cruz, California 95064, United States.
Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.


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.


bRo5; cyclic peptide; epimer; phepropeptin

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