3-Aminoxypropionate-based linker system for cyclization activation in prodrug design

Yiyu Ge; Xinghua Wu; Dazhi Zhang; Longqin Hu

doi:10.1016/j.bmcl.2008.11.097

3-Aminoxypropionate-based linker system for cyclization activation in prodrug design

Yiyu Ge
, Xinghua Wu
, Dazhi Zhang
, Longqin Hu

Ernest Mario School of Pharmacy, Medicinal Chemistry

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

A novel linker system based on 3-aminoxypropionate was designed and evaluated for drug release using proteolysis as an activation trigger followed by intramolecular cyclization. The hydroxylamine moiety present in the linker system enabled faster release of the parent drug from the linker-drug conjugate at lower pH as compared to an aliphatic amine moiety. Introduction of two methyl groups strategically at the α position to the carboxylate in the linker further improved the rate of cyclization by nearly 2-fold. The 3-aminoxypropionate linker was successfully applied to a model prodrug for protease activation using α-chymotrypsin as the activating enzyme; the activation of the model prodrug bearing the 3-aminoxypropionate linker was 136 times faster than the corresponding model prodrug bearing an amine linker.

Original language	American English
Pages (from-to)	941-944
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2008.11.097
State	Published - Feb 1 2009

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Keywords

Cancer chemotherapy
Cyclization activation
Drug design
FUDR
Hydroxylamine
Prodrug
Proteolysis
Targeted activation

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10.1016/j.bmcl.2008.11.097

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title = "3-Aminoxypropionate-based linker system for cyclization activation in prodrug design",

abstract = "A novel linker system based on 3-aminoxypropionate was designed and evaluated for drug release using proteolysis as an activation trigger followed by intramolecular cyclization. The hydroxylamine moiety present in the linker system enabled faster release of the parent drug from the linker-drug conjugate at lower pH as compared to an aliphatic amine moiety. Introduction of two methyl groups strategically at the α position to the carboxylate in the linker further improved the rate of cyclization by nearly 2-fold. The 3-aminoxypropionate linker was successfully applied to a model prodrug for protease activation using α-chymotrypsin as the activating enzyme; the activation of the model prodrug bearing the 3-aminoxypropionate linker was 136 times faster than the corresponding model prodrug bearing an amine linker.",

keywords = "Cancer chemotherapy, Cyclization activation, Drug design, FUDR, Hydroxylamine, Prodrug, Proteolysis, Targeted activation",

author = "Yiyu Ge and Xinghua Wu and Dazhi Zhang and Longqin Hu",

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AU - Ge, Yiyu

AU - Wu, Xinghua

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AU - Hu, Longqin

PY - 2009/2/1

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AB - A novel linker system based on 3-aminoxypropionate was designed and evaluated for drug release using proteolysis as an activation trigger followed by intramolecular cyclization. The hydroxylamine moiety present in the linker system enabled faster release of the parent drug from the linker-drug conjugate at lower pH as compared to an aliphatic amine moiety. Introduction of two methyl groups strategically at the α position to the carboxylate in the linker further improved the rate of cyclization by nearly 2-fold. The 3-aminoxypropionate linker was successfully applied to a model prodrug for protease activation using α-chymotrypsin as the activating enzyme; the activation of the model prodrug bearing the 3-aminoxypropionate linker was 136 times faster than the corresponding model prodrug bearing an amine linker.

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KW - Cyclization activation

KW - Drug design

KW - FUDR

KW - Hydroxylamine

KW - Prodrug

KW - Proteolysis

KW - Targeted activation

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IS - 3

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3-Aminoxypropionate-based linker system for cyclization activation in prodrug design

Abstract

ASJC Scopus subject areas

Keywords

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