Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy
| Autor: | Yvain Gerard, Sébastien Tarrit, Donia Ghedira, Elise Maubert, Elisabeth Miot-Noirault, Jean-Michel Chezal, Vincent Gaumet, Marie-Josèphe Galmier, Damien Canitrot, Aurélien Voissiere, Valérie Weber, Caroline Peyrode |
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| Přispěvatelé: | Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire de Physiologie [Monastir], Faculté de Médecine de Monastir [Tunisie], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Peyrode-Mouleyre, Caroline |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Stereochemistry
Chondrosarcoma Antineoplastic Agents Bone Neoplasms Phosphoramide [CHIM.THER]Chemical Sciences/Medicinal Chemistry Cleavage (embryo) Biochemistry 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Cell Line Tumor [CHIM] Chemical Sciences Drug Discovery medicine Humans [CHIM]Chemical Sciences Prodrugs Hypoxia-activated prodrug Quaternary ammonium Molecular Biology 030304 developmental biology Cell Proliferation 0303 health sciences Dose-Response Relationship Drug Molecular Structure Chemistry [CHIM.ORGA]Chemical Sciences/Organic chemistry Organic Chemistry Extraskeletal Myxoid Chondrosarcoma Prodrug Ligand (biochemistry) medicine.disease Phosphoramide Mustard Proteoglycan 2 030220 oncology & carcinogenesis Drug Design Proteoglycan Amine gas treating Phosphoramide Mustards Drug Screening Assays Antitumor Linker Neoplasms Connective and Soft Tissue |
| Zdroj: | Bioorganic Chemistry Bioorganic Chemistry, Elsevier, 2020, 98, pp.103747. ⟨10.1016/j.bioorg.2020.103747⟩ Bioorganic Chemistry, 2020, 98, pp.103747. ⟨10.1016/j.bioorg.2020.103747⟩ |
| ISSN: | 0045-2068 1090-2120 |
| DOI: | 10.1016/j.bioorg.2020.103747⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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