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Tunable pH-Sensitive 2-Carboxybenzyl Phosphoramidate Cleavable Linkers.

Brian S Backer¹, Cindy J Choy¹, Austen L Davis¹

¹Department of Chemistry, Washington State University, Pullman, WA, 99164-4630 U.S.A.

Tetrahedron Letters

|March 25, 2020

Summary

This study confirms that the pH-triggered release of amine-containing drugs via phosphoramidate linkers depends on the acidity (pKa) of nearby acidic groups. Modifying substituents on the linker precisely controlled this drug release pH.

Keywords:

Cleavable Linker Hammet Effects Hydrolysis Phosphoramidate

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Area of Science:

Medicinal Chemistry
Organic Chemistry
Drug Delivery

Background:

A pH-sensitive phosphoramidate linker scaffold was previously developed for tunable amine-containing drug release.
Linker tunability was initially linked to the proximity of acidic groups like carboxylic acids or pyridinium.

Purpose of the Study:

To confirm and further investigate the dependence of pH-triggered amine release on the pKa of proximal acidic groups.
To synthesize and evaluate novel 2-carboxybenzyl phosphoramidates with systematically varied pKa values.

Main Methods:

Synthesis of a series of 2-carboxybenzyl phosphoramidates.
Attenuating the pKa of the proximal benzoic acid via ring substituents.
Correlating substituent electronic effects (σ-values) with pKa modulation.

Main Results:

Confirmed that linker tunability for amine release is directly dependent on the pKa of the proximal acidic group.
Demonstrated predictable modulation of pKa through substituent effects on the benzoate ring.
Established a clear relationship between electronic properties of substituents and linker performance.

Conclusions:

The pKa of proximal acidic groups is a critical determinant for the pH-triggered release of amine-containing drugs from phosphoramidate linkers.
Substituent-controlled pKa offers a precise method for tuning drug release profiles for targeted therapies.
This work refines the design principles for advanced pH-sensitive drug delivery systems.