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

Author:

Ricardo Manuel G.123ORCID,Llanes Dayma1,Rennert Robert1,Jänicke Paul1,Rivera Daniel G.12ORCID,Wessjohann Ludger A.1ORCID

Affiliation:

1. Department of Bioorganic Chemistry Leibniz Institute of Plant Biochemistry Weinberg 3 D-06120 Halle (Saale) Germany

2. Laboratory of Synthetic and Biomolecular Chemistry Faculty of Chemistry University of Havana Zapata & G Havana 10400 Cuba

3. Present address: Department of Biomolecular Systems Max Planck Institute of Colloids and Interfaces Am Mühlenberg 1 D-14476 Potsdam Germany.

Abstract

AbstractTubulysins 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.

Funder

Bundesministerium für Bildung und Forschung

German Academic Exchange Service

Publisher

Wiley

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