- Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy
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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-trimethylpropylaminium 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.
- Canitrot, Damien,Chezal, Jean-Michel,Galmier, Marie-Josephe,Gaumet, Vincent,Gerard, Yvain,Ghedira, Donia,Maubert, Elise,Miot-Noirault, Elisabeth,Peyrode, Caroline,Tarrit, Sebastien,Voissière, Aurélien,Weber, Valérie
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supporting information
(2020/04/08)
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- SYNTHESIS AND FORMULATIONS OF SALTS OF ISOPHOSPHORAMIDE MUSTARD AND ANALOGS THEREOF
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Disclosed herein are formulations and methods of manufacture of compounds of formula (E):wherein X and Y independently represent leaving groups; and A+ is an ammonium cation.
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Page/Page column 43-44
(2010/04/03)
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- Synthesis of potential metabolites of (S)-(-)-bromofosfamide
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(S)-(-)-Bromofosfamide, a newly obtained anticancer agent, recently became a subject of phase I clinical trials in Poland. With the aim to study its metabolism in humans using phosphorus nuclear magnetic resonance a group of potential metabolites of this agent was synthesized.
- Misiura, Konrad
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p. 668 - 672
(2007/10/03)
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