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

Autor: Magali Vivier, Jean-Michel Chezal, Elise Maubert, Donia Ghedira, Elisabeth Miot-Noirault, Jamil Kraïem, Farhat Farhat, Valérie Weber, Aurélien Voissiere, Caroline Peyrode, Yvain Gerard
Přispěvatelé: Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Université de Monastir - University of Monastir (UM), COLO, Mouniati
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
medicine.medical_treatment
Chondrosarcoma
Antineoplastic Agents
Bone Neoplasms
[SDV.CAN]Life Sciences [q-bio]/Cancer
[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
Targeted therapy
Extracellular matrix
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
[SDV.CAN] Life Sciences [q-bio]/Cancer
Cell Line
Tumor
Drug Discovery
medicine
Humans
Structure–activity relationship
Prodrugs
Aggrecans
Molecular Targeted Therapy
Hypoxia-activated prodrug
Quaternary ammonium
Cytotoxicity
Aggrecan
Cell Proliferation
Pharmacology
biology
Chemistry
Organic Chemistry
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
General Medicine
Prodrug
medicine.disease
3. Good health
Oxygen
Quaternary Ammonium Compounds
030104 developmental biology
Proteoglycan
030220 oncology & carcinogenesis
Cancer research
biology.protein
Tumor Hypoxia
Proteoglycans
Zdroj: European Journal of Medicinal Chemistry
European Journal of Medicinal Chemistry, Elsevier, 2018, 158, pp.51-67. ⟨10.1016/j.ejmech.2018.08.060⟩
ISSN: 0223-5234
1768-3254
DOI: 10.1016/j.ejmech.2018.08.060⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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