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Pharmacomodulation of the linker tethered the FDG tumor-seeking group and the alkylating N-mustard leads to compound 51, identified as the most active FDG-CLB glucoside by in vitro cytotoxicity assays against different human normal and tumor cell lines.
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•Chlorambucil was conjugated to FDG for tumor-targeting drug delivery.•A novel series of sixteen fluoroglucoconjugates of N-mustard was synthesized.•In vitro cytotoxicities against a panel of human tumor cell lines were evaluated.•The study highlights the positive impact of an aromatic amide linker.•Compound 51 was identified as the most potent cytotoxic glucoside.
Nitrogen mustards, such as chlorambucil (CLB), can cause adverse side-effects due to ubiquitous distribution in non-target organs. To minimize this toxicity, strategies of tumor-targeting drug delivery have been developed, where a cytotoxic warhead is linked to a tumor-cell-specific small ligand. Malignant cells exhibit marked glucose avidity and an accelerated metabolism by aerobic glycolysis, known as the Warburg effect, and recognized as a hallmark of cancer. A targeting approach exploiting the Warburg effect by conjugation of CLB to 2-fluoro-2-deoxyglucose (FDG) was previously reported and identified two peracetylated glucoconjugates 2 and 3 with promising antitumor activities in vivo. These results prompted us to investigate the importance of the spacer in this tumor-targeting glucose-based conjugates. Here we report the chemical synthesis and an in vitro cytotoxicity evaluation, using a 5-member panel of human tumor cell lines and human fibroblasts, of 16 new CLB glucoconjugates in which the alkylating drug is attached to the C-1 position of FDG via different linkages. We studied the structure-activity relationships in the linker, and evidenced the positive impact of an aromatic linker on in vitro cytotoxicity: compound 51 proved to be the most active FDG-CLB glucoside, characterized by a bis-aromatic spacer tethered to CLB through an amide function.