Synthesis and Biological Characterization of Monomeric and Tetrameric RGD-Cryptophycin Conjugates.

Adina Borbély, Fabien Thoreau, Eduard Figueras, Malika Kadri, Jean-Luc Coll, Didier Boturyn, Norbert Sewald

Chemistry (Weinheim an der Bergstrasse, Germany) 2020 Feb 26

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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 αv β3 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 αv β3 overexpressing tumor cell lines, while significantly reduced activity was observed in the integrin-negative cell line. © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Citation

Adina Borbély, Fabien Thoreau, Eduard Figueras, Malika Kadri, Jean-Luc Coll, Didier Boturyn, Norbert Sewald. Synthesis and Biological Characterization of Monomeric and Tetrameric RGD-Cryptophycin Conjugates. Chemistry (Weinheim an der Bergstrasse, Germany). 2020 Feb 26;26(12):2602-2605