Amino DSA analogues as payloads for antibody-drug conjugates with multiple sites for conjugation. Initial studies and solid phase synthesis

Research output: Contribution to journalArticle

Abstract

Duocarmycins are highly potent and promising anticancer payloads for ADC applications. They tolerate a range of chemical modifications which allow the chemist to modulate both their biophysical and pharmacological properties. The possibility to synthesize these payloads on resin and orthogonally add linkers while immobilized on the solid phase, would allow a combinatorial design of payload analogues with linkers, potentially aided by automation. Working towards this goal, we report a concise and high yielding synthesis of an alkylating unit suitable for solid phase synthesis (10, 9 steps, 34% yield) and demonstrate its applicability to the synthesis of duocarmycin SA analogues (19, 20). An intermediate for traditional solution phase synthesis (8) is also described in 7 steps and 44% yield. A side reaction with potential application to the stereoselective synthesis of these derivatives has also been described.

Original languageEnglish
Article number153058
JournalTetrahedron Letters
Volume72
Early online date6 Apr 2021
DOIs
Publication statusPublished - 25 May 2021

Keywords

  • Antibody drug conjugate
  • Duocarmycin
  • Natural product
  • Solid phase
  • Yatakemycin

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