| Autor: |
Ahangarpour M; School of Chemical Sciences, The University of Auckland, 23 Symonds St., Auckland 1010, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand., Brimble MA; School of Chemical Sciences, The University of Auckland, 23 Symonds St., Auckland 1010, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand.; School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand., Kavianinia I; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand.; School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand. |
| Abstrakt: |
The synthesis of linker-payloads is a critical step in developing antibody-drug conjugates (ADCs), a rapidly advancing therapeutic approach in oncology. The conventional method for synthesizing cathepsin B-labile dipeptide linkers, which are commonly used in ADC development, involves the solution-phase assembly of cathepsin B-sensitive dipeptides, followed by the installation of self-immolative para -aminobenzyl carbonate to facilitate the attachment of potent cytotoxic payloads. However, this approach is often low yield and laborious, especially when extending the peptide chain with components like glutamic acid to improve mouse serum stability or charged amino acids or poly(ethylene glycol) moieties to enhance linker hydrophilicity. Here, we introduce a novel approach utilizing late-stage desulfurization chemistry, enabling safe, facile, and cost-effective access to the cathepsin B-cleavable linker, Val-Ala-PABC-MMAE, on resin for the first time. |
