Synthesis and cytotoxic properties of new fluorodeoxyglucose-coupled chlorambucil derivatives

Bioorganic & Medicinal Chemistry
Bastien ReuxPascal Coudert

Abstract

Frequently used in the treatment of malignant cells, alkylating agents, like most anticancer substances, produce adverse side effects caused by the toxicity of the agents toward normal tissues and lose efficiency through poor distribution to target sites. Our approach to developing more selective drugs with low systemic toxicity is based on the premise that the body distribution and cell uptake of a drug can be altered by attaching a neoplastic cell-specific uptake enhancer, such as 2-fluoro-2-deoxyglucose (FDG), the radiotracer most frequently used in PET for tumor imaging. Two properties of deoxyglucose, namely preferential accumulation in neoplastic cells and inhibition of glycolysis, underpin this targeting approach. Here, we report the synthesis of 19 new chlorambucil glycoconjugates in which the alkylating drug is attached to the C-1 position of FDG, directly or via different linkages. This set of compounds was evaluated for in vitro cytotoxicity against different human normal and tumor cell lines. There was a significant improvement in the in vitro cytotoxicity of peracetylated glucoconjugates compared with the free substance. Four compounds were finally selected for further in vivo studies owing to their lack of oxidati...Continue Reading

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Citations

Oct 27, 2010·Journal of Medicinal Chemistry·Randal D Goff, Jon S Thorson
Jul 21, 2015·Chemistry and Physics of Lipids·Temilolu IdowuFrank Schweizer
May 3, 2011·European Journal of Medicinal Chemistry·Pierre DaumarMarie-Josèphe Galmier
Nov 22, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·HongYan ZhuWei Zhang
Oct 2, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Yingyue ZhangKathryn E Uhrich
Mar 19, 2016·Medicinal Research Reviews·Chin S KueHong B Lee
Mar 17, 2015·European Journal of Medicinal Chemistry·Yuan-Zhen XuKun Gao
Oct 1, 2013·Chemical Science·Emilia C Calvaresi, Paul J Hergenrother
Feb 12, 2013·Cancer Research·Jie CaoGuangji Wang
Jun 3, 2021·International Journal of Molecular Sciences·Nazanin NahrjouMarina Tanasova
Nov 30, 2011·Bioconjugate Chemistry·Annalisa GuaragnaGiovanni Palumbo

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