Details

Autor(en) / Beteiligte

• Le Roux, Antoine
• Blaise, Émilie
• Boudreault, Pierre-Luc
• Comeau, Christian
• Doucet, Annie
• Giarrusso, Marilena
• Collin, Marie-Pierre
• Neubauer, Thomas
• Kölling, Florian
• Göller, Andreas H
• Seep, Lea
• Tshitenge, Dieudonné T
• Wittwer, Matthias
• Kullmann, Maximilian
• Hillisch, Alexander
• Mittendorf, Joachim
• Marsault, Eric

Titel

Structure–Permeability Relationship of Semipeptidic MacrocyclesUnderstanding and Optimizing Passive Permeability and Efflux Ratio

Ist Teil von

• Journal of medicinal chemistry, 2020-07, Vol.63 (13), p.6774-6783

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• We herein report the first thorough analysis of the structure–permeability relationship of semipeptidic macrocycles. In total, 47 macrocycles were synthesized using a hybrid solid-phase/solution strategy, and then their passive and cellular permeability was assessed using the parallel artificial membrane permeability assay (PAMPA) and Caco-2 assay, respectively. The results indicate that semipeptidic macrocycles generally possess high passive permeability based on the PAMPA, yet their cellular permeability is governed by efflux, as reported in the Caco-2 assay. Structural variations led to tractable structure–permeability and structure–efflux relationships, wherein the linker length, stereoinversion, N-methylation, and peptoids site-specifically impact the permeability and efflux. Extensive nuclear magnetic resonance, molecular dynamics, and ensemble-based three-dimensional polar surface area (3D-PSA) studies showed that ensemble-based 3D-PSA is a good predictor of passive permeability.