We propose to use highly substituted crown ethers to mimic the action of two classes of biomolecules: the sulfhydryl hydrolases; and transmembrane ion channels.
We aim to synthesize and use highly functionalized 18-crown-6 derivatives 1 to model the sequence of steps involved in the action of the sulfhydryl proteases and transferases. The compounds were designed with the aid of Corey-Pauling-Koultun (CPK) models to efficiently bind alpha-amino acid ester hydrobromides, and to enhance the solvolysis of these. The model bears six substituents attached to six chiral carbons of known absolute configuration. Four of the substituents are functional: two CR2SH groups bear the nucleophilic sulfur atom to attack the carbonyl of bound substrate; two hydroxymethyls to provide hydrogen bonding possibilities to the presumed transition states leading to the tetrahedral intermediates. All six substituents are conformationally important, we propose, as they assist in making the uncomplexed 18-crown-6 nucleus less mobile than less substituted crowns, providing a degree of preorganization to 1. Crown ethers 2-6 will also be prepared. Crowns 2-5 are necessary to help determine the contribution(s) which the various functional or structural groups (and their positions around the crown) in 1 make in the efficacy of this compound as an enzyme mimic. Crown 6 (R=H) is a known compound previously used as a sulfhydryl transferase mimic, and will serve as a reference to which crowns 1-5 will be compared. The rates of solvolysis of alpha-amino acid ester hydrobromides in the presence of each of the crowns 1-6 will be compared. Crown ether 7 is proposed as a model for a trans-membrane ion channel. The core of it is an 18-crown-6 nucleus bearing six pendant polyether chains terminating in carboxyl groups. Each of these chains bear an amino acid residue. The three polyether chains on each side of the crown ether nucleus would be circularly organized by three-inter chain hydrogen bonds (among the amino acid residues) forming the crude channel model. The ability of this molecule to transport ions across a membrane will be evaluated.
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