Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma

Abstract : Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumour, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumour, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high negative fixed charge density and severe chronic hypoxia. A dual targeted therapy for chondrosarcoma was investigated by conjugation of a hypoxia-activated prodrug (HAP) to quaternary ammonium (QA) functions which exhibit a high affinity for polyanionic sites of proteoglycans (PGs), the major components of the chondrosarcoma extracellular matrix. Based on preclinical results, an imidazole prodrug, ICF05016, was identified and provided the basis for a lead optimization study. A series of 27 QA-phosphoramide mustard conjugates, differing by the type of QA function and the length of the alkyl linker, was yielded by a common multi-step sequence involving phosphorylation of a key 2-nitroimidazole alcohol. Then, a screening was realized by surface plasmon resonance technology to assess biomolecular interactions between QA derivatives and aggrecan, the most abundant PG in chondrosarcoma. Results revealed that affinity depends more on the type of QA function, than on the linker length. Moreover, the presence of a benzyl group enhanced affinity to aggrecan. Twelve compounds were shortlisted and evaluated for antiproliferative activity (i.e., growth inhibiting concentration 50), under normoxic and hypoxic conditions using the human extraskeletal myeloid chondrosarcoma cell line (HEMC-SS). For all prodrugs, hypoxic selectivity was maintained and even increased, compared with the lead. From this study, compound 31f emerged as the most effective PG-targeted HAPs with a dissociation constant of 2.10 μM in the SPR experiment, a hypoxia cytotoxicity ratio of 24 and an efficient reductive cleavage under chemical and enzymatic conditions.
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https://hal.archives-ouvertes.fr/hal-01926337
Contributor : Mouniati Colo <>
Submitted on : Monday, November 19, 2018 - 10:44:50 AM
Last modification on : Thursday, March 7, 2019 - 11:46:54 AM

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Donia Ghedira, Aurélien Voissiere, Caroline Peyrode, Jamil Kraiem, Yvain Gerard, et al.. Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma. European Journal of Medicinal Chemistry, Elsevier, 2018, 158, pp.51 - 67. ⟨10.1016/j.ejmech.2018.08.060⟩. ⟨hal-01926337⟩

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