Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug

Irene G. Boutselis, Xiao Yu, Zhong-Yin Zhang, Richard F. Borch

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Our laboratory recently reported the development of novel prodrug chemistry for the intracellular delivery of phosphotyrosine mimetics. This chemistry has now been adapted for the synthesis of a prodrug that delivers the nonhydrolyzable difluoromethylphosphonate moiety intracellularly. Activation of the prodrug generates a difluoromethylphosphonamidate anion that undergoes subsequent cyclization and hydrolysis with a t1/2 = 44 min. A highly potent and selective inhibitor of protein tyrosine phosphatase 1B (PTP1B) with a nanomolar Ki has been reported, but this bis(difluoromethylphosphonate) lacks potential utility due to its exceedingly low membrane permeability at physiological pH. A prodrug of this inhibitor has been synthesized and evaluated in a cell-based assay. The prodrug exhibits nanomolar PTP1B inhibitory activity in this assay, confirming the efficacy of intracellular phosphonate delivery using this prodrug approach.

Original languageEnglish
Pages (from-to)856-864
Number of pages9
JournalJournal of Medicinal Chemistry
Volume50
Issue number4
DOIs
StatePublished - Feb 22 2007

Fingerprint

Non-Receptor Type 1 Protein Tyrosine Phosphatase
Prodrugs
Assays
Organophosphonates
Phosphotyrosine
Cyclization
Anions
Hydrolysis
Permeability
Chemical activation
Membranes

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug. / Boutselis, Irene G.; Yu, Xiao; Zhang, Zhong-Yin; Borch, Richard F.

In: Journal of Medicinal Chemistry, Vol. 50, No. 4, 22.02.2007, p. 856-864.

Research output: Contribution to journalArticle

@article{c0004783e16741e5941b291859ed550f,
title = "Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug",
abstract = "Our laboratory recently reported the development of novel prodrug chemistry for the intracellular delivery of phosphotyrosine mimetics. This chemistry has now been adapted for the synthesis of a prodrug that delivers the nonhydrolyzable difluoromethylphosphonate moiety intracellularly. Activation of the prodrug generates a difluoromethylphosphonamidate anion that undergoes subsequent cyclization and hydrolysis with a t1/2 = 44 min. A highly potent and selective inhibitor of protein tyrosine phosphatase 1B (PTP1B) with a nanomolar Ki has been reported, but this bis(difluoromethylphosphonate) lacks potential utility due to its exceedingly low membrane permeability at physiological pH. A prodrug of this inhibitor has been synthesized and evaluated in a cell-based assay. The prodrug exhibits nanomolar PTP1B inhibitory activity in this assay, confirming the efficacy of intracellular phosphonate delivery using this prodrug approach.",
author = "Boutselis, {Irene G.} and Xiao Yu and Zhong-Yin Zhang and Borch, {Richard F.}",
year = "2007",
month = "2",
day = "22",
doi = "10.1021/jm061146x",
language = "English",
volume = "50",
pages = "856--864",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug

AU - Boutselis, Irene G.

AU - Yu, Xiao

AU - Zhang, Zhong-Yin

AU - Borch, Richard F.

PY - 2007/2/22

Y1 - 2007/2/22

N2 - Our laboratory recently reported the development of novel prodrug chemistry for the intracellular delivery of phosphotyrosine mimetics. This chemistry has now been adapted for the synthesis of a prodrug that delivers the nonhydrolyzable difluoromethylphosphonate moiety intracellularly. Activation of the prodrug generates a difluoromethylphosphonamidate anion that undergoes subsequent cyclization and hydrolysis with a t1/2 = 44 min. A highly potent and selective inhibitor of protein tyrosine phosphatase 1B (PTP1B) with a nanomolar Ki has been reported, but this bis(difluoromethylphosphonate) lacks potential utility due to its exceedingly low membrane permeability at physiological pH. A prodrug of this inhibitor has been synthesized and evaluated in a cell-based assay. The prodrug exhibits nanomolar PTP1B inhibitory activity in this assay, confirming the efficacy of intracellular phosphonate delivery using this prodrug approach.

AB - Our laboratory recently reported the development of novel prodrug chemistry for the intracellular delivery of phosphotyrosine mimetics. This chemistry has now been adapted for the synthesis of a prodrug that delivers the nonhydrolyzable difluoromethylphosphonate moiety intracellularly. Activation of the prodrug generates a difluoromethylphosphonamidate anion that undergoes subsequent cyclization and hydrolysis with a t1/2 = 44 min. A highly potent and selective inhibitor of protein tyrosine phosphatase 1B (PTP1B) with a nanomolar Ki has been reported, but this bis(difluoromethylphosphonate) lacks potential utility due to its exceedingly low membrane permeability at physiological pH. A prodrug of this inhibitor has been synthesized and evaluated in a cell-based assay. The prodrug exhibits nanomolar PTP1B inhibitory activity in this assay, confirming the efficacy of intracellular phosphonate delivery using this prodrug approach.

UR - http://www.scopus.com/inward/record.url?scp=33847383241&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847383241&partnerID=8YFLogxK

U2 - 10.1021/jm061146x

DO - 10.1021/jm061146x

M3 - Article

C2 - 17249650

AN - SCOPUS:33847383241

VL - 50

SP - 856

EP - 864

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 4

ER -