Bockus Andrew T, Lexa Katrina W, Pye Cameron R, Kalgutkar Amit S, Gardner Jarret W, Hund Kathryn C R, Hewitt William M, Schwochert Joshua A, Glassey Emerson, Price David A, Mathiowetz Alan M, Liras Spiros, Jacobson Matthew P, Lokey R Scott
†Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
‡Department of Pharmaceutical Chemistry, University of California- San Francisco, 1700 4th Street, San Francisco, California 94158, United States.
J Med Chem. 2015 Jun 11;58(11):4581-9. doi: 10.1021/acs.jmedchem.5b00128. Epub 2015 May 20.
Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation. Here we report the synthesis of cyclic hexapeptide diastereomers containing γ-amino acids (e.g., statines) and systematically investigate their structure-permeability relationships. These compounds were much more water-soluble and, in many cases, were both more membrane permeable and more stable to liver microsomes than a similar non-statine-containing derivative. Permeability correlated well with the extent of intramolecular hydrogen bonding observed in the solution structures determined in the low-dielectric solvent CDCl3, and one compound showed an oral bioavailability of 21% in rat. Thus, the incorporation of γ-amino acids offers a route to increase backbone diversity and improve ADME properties in cyclic peptide scaffolds.
环肽天然产物含有多种保守的、非蛋白质ogenic结构元件，如d-氨基酸和酰胺N-甲基化。此外，许多环肽还包含γ-氨基酸和其他源自聚酮合酶的元件。我们假设这些扩展主链元件的位置和方向会影响这些杂合分子的ADME性质，特别是它们穿过细胞膜和避免代谢降解的能力。在此，我们报告了含有γ-氨基酸（如他汀类）的环六肽非对映异构体的合成，并系统地研究了它们的结构-渗透性之间的关系。这些化合物的水溶性更高，而且在许多情况下，与类似的不含他汀类的衍生物相比，它们对肝微粒体的膜渗透性更高，稳定性也更高。渗透性与在低介电溶剂CDCl3中测定的溶液结构中观察到的分子内氢键程度密切相关，并且一种化合物在大鼠中显示出21%的口服生物利用度。因此，γ-氨基酸的掺入为增加环肽支架中的主链多样性和改善ADME性质提供了一条途径。
