title: Synthesis and cytotoxic properties of new fluorodeoxyglucose-coupled chlorambucil derivatives.
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 oxidative stress-inducing properties.
authors.affiliation: Univ Clermont 1, UFR Pharmacie/Médecine, Clermont-Ferrand F-63001, France.
authors.forename: Bastien
authors.initials: B
authors.lastname: Reux
authors.forename: Valérie
authors.initials: V
authors.lastname: Weber
authors.forename: Marie-Josephe
authors.initials: MJ
authors.lastname: Galmier
authors.forename: Michèle
authors.initials: M
authors.lastname: Borel
authors.forename: Michel
authors.initials: M
authors.lastname: Madesclaire
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Madelmont
authors.forename: Eric
authors.initials: E
authors.lastname: Debiton
authors.forename: Pascal
authors.initials: P
authors.lastname: Coudert
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002699:Chlorambucil / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D019788:Fluorodeoxyglucose F18 / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D019788:Fluorodeoxyglucose F18; D002699:Chlorambucil