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Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy

Abstract : The tumor microenvironment in chondrosarcoma (CHS), a chemo-and radio-resistant cancer provides unique hallmarks for developing a chondrosarcoma targeted drug-delivery system. Tumor targeting could be achieved using a quaternary ammonium function (QA) as a ligand for aggrecan, the main high negative charged proteoglycan of the extracellular matrix of CHS, and a 2-nitroimidazole as trigger that enables hypoxia-responsive drug release. In a previous work, ICF05016 was identified as efficient proteoglycan-targeting hypoxia-activated prodrug in a human extraskeletal myxoid chondrosarcoma model in mice and a first study of the structure-activity relationship of the QA function and the alkyl linker length was conducted. Here, we report the second part of the study, namely the modification of the nitro-aromatic trigger and the position of the proteoglycan-targeting ligand at the aromatic ring as well as the nature of the alkylating mustard. Synthetic approaches have been established to functionalize the 2-nitroimidazole ring at the N-1 and C-4 positions with a terminal tertiary alkyl amine, and to perform the phosphorylation step namely through the use of an amine borane complex, leading to phosphoramide and isophosphoramide mustards and also to a phosphoramide mustard bearing four 2-chloroethyl chains. In a preliminary study using a reductive chemical activation, QA-conjugates, except the 4-nitrobenzyl one, were showed to undergo efficient cleavage with release of the corresponding mustard. However N,N,N-trimethylpropylamimium tethered to the N-1 or C-4 positions of the imidazole seemed to hamper the enzymatic reduction of the prodrugs and all tested compounds featured moderate selectivity toward hypoxic cells, likely not sufficient for application as hypoxia-activated prodrugs.
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Submitted on : Thursday, November 19, 2020 - 12:09:36 PM
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yvain Gerard, Aurélien Voissiere, Caroline Peyrode, Marie-Josephe Galmier, Elise Maubert, et al.. Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy. Bioorganic Chemistry, Elsevier, 2020, 98, pp.103747. ⟨10.1016/j.bioorg.2020.103747⟩. ⟨hal-02866765⟩



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