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-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.

• Authors: Yvain Gerard, Aurélien Voissière, Caroline Peyrode, Marie-Josephe Galmier, Elise Maubert, Donia Ghedira, Sebastien Tarrit, Vincent Gaumet, Damien Canitrot, Elisabeth Miot-Noirault, Jean-Michel Chezal, Valérie Weber
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 98 Pg. 103747 (05 2020) ISSN: 1090-2120 [Electronic] United States
• PMID: 32208207 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Phosphoramide Mustards
• Prodrugs
• phosphoramide mustard
• isophosphamide mustard

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Bone Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chondrosarcoma (drug therapy, pathology)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Molecular Structure
• Neoplasms, Connective and Soft Tissue (drug therapy, pathology)
• Phosphoramide Mustards (chemical synthesis, chemistry, pharmacology)
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship