103151-96-8Relevant academic research and scientific papers
Linker structure-activity relationships in fluorodeoxyglucose chlorambucil conjugates for tumor-targeted chemotherapy
El Hilali, Mostafa,Reux, Bastien,Debiton, Eric,Leal, Fernand,Galmier, Marie-Josephe,Vivier, Magali,Chezal, Jean-Michel,Miot-Noirault, Elisabeth,Coudert, Pascal,Weber, Valérie
, p. 5692 - 5708 (2017)
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.
