Synthesis and study of a new bioorthogonal self-immolative linker based on the Grob fragmentation reaction

  1. M. Salas-Cubero 1
  2. X. Ferhati 1
  3. P. Garrido 2
  4. J. García-Sanmartín 2
  5. A. Guerreiro 3
  6. A. Avenoza 1
  7. J.H. Busto 1
  8. J.M. Peregrina 1
  9. A. Martínez 2
  10. E. Jiménez-Moreno 1
  11. G.J.L. Bernardes 34
  12. F. Corzana 1
  1. 1 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  2. 2 Centro de Investigación Biomédica de La Rioja
    info

    Centro de Investigación Biomédica de La Rioja

    Logroño, España

    ROR https://ror.org/03vfjzd38

  3. 3 Universidade de Lisboa
    info

    Universidade de Lisboa

    Lisboa, Portugal

    ROR https://ror.org/01c27hj86

  4. 4 University of Cambridge
    info

    University of Cambridge

    Cambridge, Reino Unido

    ROR https://ror.org/013meh722

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Proceedings:
XXXVIII Reunión Bienal de la Real Sociedad Española de Química - RSEQ 2022 (Abstracts book)

Publisher: Universidad de Granada

ISBN: 978-84-09-42159-6

Year of publication: 2022

Pages: 645

Congress: XXXVIII Reunión Bienal de la Real Sociedad Española de Química (RSEQ Granada 2021) 27-30 de junio de 2022

Type: Conference paper

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Abstract

Cleavable linkers are designed to release the drug within or in the vicinity of the tumour cells upon a trigger stimulus. In recent years, there have been multiple reports of self-immolative cleavable linkers able to self-degrade in a spontaneous and irreversible manner through a cascade-elimination process. In general, this process is driven by an entropy increase and the formation of thermodynamically stable products and the control of the drug release is achieved by a stimulus such as an enzymatic cleavage of the linker that activates the self-immolative process. [1]We have designed and synthesized a new self-immolative bioorthogonal conditionally cleavable linker based on the Grob fragmentation that allowed the controlled release of sulfonate-containing compounds such as a dansyl group under physiological conditions. We have also tuned conveniently the pKa of the pushing group (amino group) using different substituents, leading to more efficient conversions at physiological pH and in some cases even at acidic pH, which is normally found in tumour environments. In addition, the Grob fragmentation takes place under physiological conditions in living cells, demonstrating the potential bioorthogonal applicability of the reaction. Based on these promising results, research is currently underway to incorporate this type of linker into antibody−drug conjugates for the targeted delivery of cytotoxic drugs and fluorophores.