Abstract
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.
| Original language | English |
|---|---|
| Journal | ChemMedChem |
| Early online date | 26 Nov 2019 |
| DOIs | |
| Publication status | E-pub ahead of print - 26 Nov 2019 |
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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 journal › Article
TY - JOUR
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
PY - 2019/11/26
Y1 - 2019/11/26
N2 - 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.
AB - 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.
KW - endoperoxides
KW - carbohydrate chemotherapeutics
KW - DNA damage
KW - hypoxia
KW - photochemistry
UR - http://www.scopus.com/inward/record.url?scp=85076021833&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201900578
DO - 10.1002/cmdc.201900578
M3 - Article
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
ER -