Improved Access to Potent Anticancer Tubulysins and Linker-Functionalized Payloads Via an All-On-Resin Strategy.

Autor: Ricardo MG; Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle (Saale), Germany.; Laboratory of Synthetic and Biomolecular Chemistry, Faculty of Chemistry, University of Havana, Zapata & G, Havana, 10400, Cuba.; Present address: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, D-14476, Potsdam, Germany., Llanes D; Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle (Saale), Germany., Rennert R; Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle (Saale), Germany., Jänicke P; Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle (Saale), Germany., Rivera DG; Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle (Saale), Germany.; Laboratory of Synthetic and Biomolecular Chemistry, Faculty of Chemistry, University of Havana, Zapata & G, Havana, 10400, Cuba., Wessjohann LA; Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle (Saale), Germany.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2024 Jul 25; Vol. 30 (42), pp. e202401943. Date of Electronic Publication: 2024 Jul 05.
DOI: 10.1002/chem.202401943
Abstrakt: Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide-drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on simplifying their structures, e. g., by using small tertiary amide N-substituents (Me, Et, Pr) on the tubuvaline residue. Cumbersome solution-phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p-Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all-on-resin strategy permitting a loss-free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on-resin tubulysin derivatization with, e. g., a maleimido-Val-Cit-PABQ linker, which is a notable progress for the payload-PABQ-linker technology. The strategy also allows tubulysin diversification of the internal amide N-substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker-attachment and functionalization.
(© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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