Abstract
Phosphate and phosphonates containing a single P[sbnd]N bond are frequently used pro-drug motifs to improve cell permeability of these otherwise anionic moieties. Upon entry into the cell, the P[sbnd]N bond is cleaved by phosphoramidases to release the active agent. Here, we apply a novel mono-amidation strategy to our laboratory's phosphonate-containing glycolysis inhibitor and show that a diverse panel of phosphonoamidates may be rapidly generated for in vitro screening. We show that, in contrast to the canonical L-alanine or benzylamine moieties which have previously been reported as efficacious pro-drug moieties, small and long-chain aliphatic amines demonstrate greater drug release efficacy for our phosphonate inhibitor. These results expand the scope of possible amine pro-drugs that can be used as second pro-drug leave groups for phosphate or phosphonate-containing drugs.
Original language | English (US) |
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Article number | 127656 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 30 |
Issue number | 24 |
DOIs | |
State | Published - Dec 15 2020 |
Keywords
- Glycolysis inhibitor
- Phosphoramidase
- Pro-drug
- Structure-activity relationship
- Targeted therapy
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry