1. Academic Validation
  2. Aliphatic amines are viable pro-drug moieties in phosphonoamidate drugs

Aliphatic amines are viable pro-drug moieties in phosphonoamidate drugs

  • Bioorg Med Chem Lett. 2020 Dec 15;30(24):127656. doi: 10.1016/j.bmcl.2020.127656.
Victoria C Yan 1 Cong-Dat Pham 2 Kenisha Arthur 1 Kristine L Yang 1 Florian L Muller 1
Affiliations

Affiliations

  • 1 Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 2 Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: phamcdat@hotmail.de.
Abstract

Phosphate and phosphonates containing a single PN bond are frequently used pro-drug motifs to improve cell permeability of these otherwise anionic moieties. Upon entry into the cell, the PN 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.

Keywords

Glycolysis inhibitor; Phosphoramidase; Pro-drug; Structure-activity relationship; Targeted therapy.

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