An iterative in silico and modular synthetic approach to aqueous soluble tercyclic α-helix mimetics.
Tercyclic scaffolds, designed to have improved synthetic accessibility and aqueous solubility, were evaluated as structural α-helix mimetics by using an iterative in silico approach. The synthesis of these tercyclic scaffolds was accomplished using a modular synthetic approach by employing functionalised methoxyphenyl units which were readily manipulated to allow the introduction of various nitrogen-based heterocycles. The ability of these scaffolds to mimic the key i, i + 3 and i + 7 residues of a polyalanine α-helix was ratified by in silico studies, X-ray crystallographic and NOESY analysis, and their aqueous solubility was measured by a kinetic turbidimetric method.
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia. Kellie.Tuck@monash.edu.
Zelong
Z
Lim
Peter J
PJ
Duggan
Adam G
AG
Meyer
Kellie L
KL
Tuck
D003198:Computer Simulation; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D012995:Solubility; D013816:Thermodynamics; D014867:Water
D010455:Peptides; D014867:Water; C019529:polyalanine