Revisiting Bromo-Hexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy

Henrik Johansson, Omar Hussain, Simon J. Allison, Tony V. Robinson, Roger Phillips, Daniel Sejer Pedersen

Research output: Contribution to journalArticle

Abstract

Bromo-hexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structureactivity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window by
rational drug design or by using a pro-drug approach to exploit differences in tumour physiology compared to healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromo-hexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs
Original languageEnglish
JournalChemMedChem
Early online date26 Nov 2019
DOIs
Publication statusE-pub ahead of print - 26 Nov 2019

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Prodrugs
Neoplasms
Stereochemistry
Drug Design
Physiology
Cytotoxicity
Tumors
Therapeutics
Cells
Carbohydrates
Tissue
Derivatives
Safety
DNA
Pharmaceutical Preparations
hexitol

Cite this

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abstract = "Bromo-hexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structureactivity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window byrational drug design or by using a pro-drug approach to exploit differences in tumour physiology compared to healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromo-hexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs",
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Revisiting Bromo-Hexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy. / Johansson, Henrik; Hussain, Omar; Allison, Simon J.; Robinson, Tony V.; Phillips, Roger; Pedersen, Daniel Sejer.

In: ChemMedChem, 26.11.2019.

Research output: Contribution to journalArticle

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T1 - Revisiting Bromo-Hexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy

AU - Johansson, Henrik

AU - Hussain, Omar

AU - Allison, Simon J.

AU - Robinson, Tony V.

AU - Phillips, Roger

AU - Pedersen, Daniel Sejer

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