Synthesis and Biological Characterization of Monomeric and Tetrameric RGD-Cryptophycin Conjugates
| Autor: | Fabien Thoreau, Jean-Luc Coll, Eduard Figueras, Didier Boturyn, Adina Borbély, Malika Kadri, Norbert Sewald |
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| Přispěvatelé: | Département de Chimie Moléculaire (DCM), Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département de Chimie Moléculaire - Ingéniérie et Intéractions BioMoléculaires (DCM - I2BM), Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2019 |
| Předmět: |
Alpha-v beta-3
Integrin [CHIM.THER]Chemical Sciences/Medicinal Chemistry 010402 general chemistry 01 natural sciences Peptides Cyclic Catalysis antitumor agents chemistry.chemical_compound Cell Line Tumor Depsipeptides [CHIM]Chemical Sciences Humans Molecular Targeted Therapy Cytotoxicity small-molecule drug conjugates Drug Carriers biology 010405 organic chemistry Chemistry [CHIM.ORGA]Chemical Sciences/Organic chemistry Communication Organic Chemistry General Chemistry multivalency Ligand (biochemistry) Integrin alphaVbeta3 Communications 3. Good health 0104 chemical sciences Drug Liberation Cryptophycin Drug delivery drug delivery Biophysics biology.protein integrins Linker Medicinal Chemistry | Hot Paper Conjugate |
| Zdroj: | Chemistry (Weinheim an Der Bergstrasse, Germany) Chemistry-A European Journal Chemistry-A European Journal, Wiley-VCH Verlag, 2020, 26 (12), pp.2602-2605. ⟨10.1002/chem.201905437⟩ |
| ISSN: | 1521-3765 0947-6539 |
| DOI: | 10.1002/chem.201905437⟩ |
| Popis: | The effective delivery of cytotoxic agents to tumor cells is a key challenge in anticancer therapy. Multivalent integrinspecific ligands are considered a promising tool to increase the binding affinity, selectivity, and internalization efficiency of small‐molecule drug conjugates. Herein, we report the synthesis and biological evaluation of a multimeric conjugate containing the high‐affinity integrin αvβ3 binding ligand RAFT‐c(RGDfK)4, a lysosomally cleavable Val‐Cit linker, and cryptophycin‐55 glycinate, a potent inhibitor of tubulin polymerization. In vitro cytotoxicity assays verified that the multimeric RGD‐cryptophycin conjugate displays improved potency compared to the monomeric analogue in integrin αvβ3 overexpressing tumor cell lines, while significantly reduced activity was observed in the integrin‐negative cell line. Antitumor agents: Conjugation of cryptophycin with a multivalent integrin‐specific ligand is a powerful approach to increase the selectivity and internalization efficiency of small molecule‐drug conjugates (see figure). |
| Databáze: | OpenAIRE |
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