An iterative in silico and modular synthetic approach to aqueous soluble tercyclic α-helix mimetics?

Organic & Biomolecular Chemistry Pub Date: 2014-05-21 DOI: 10.1039/C4OB00647J

Abstract

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.

Graphical abstract: An iterative in silico and modular synthetic approach to aqueous soluble tercyclic α-helix mimetics
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