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Revisiting Bromohexitols as a Novel Class of Microenvironment‐Activated Prodrugs for Cancer Therapy
Author(s) -
Johansson Henrik,
Hussain Omar,
Allison Simon J.,
Robinson Tony V.,
Phillips Roger M.,
Sejer Pedersen Daniel
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900578
Subject(s) - prodrug , chemistry , tumor microenvironment , drug , cytotoxicity , cancer cell , hypoxia (environmental) , cancer therapy , cancer treatment , cancer , biochemistry , cancer research , pharmacology , biology , tumor cells , in vitro , organic chemistry , genetics , oxygen
Bromohexitols represent a potent class of DNA‐alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structure−activity 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 prodrug approach to exploit differences between tumour physiology and healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromohexitol 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.