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Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study

Journal Article


Abstract


  • Amide- and ester-linked kinase inhibitor-cytotoxin conjugates were rationally designed and synthesised as prototype hypoxia-activated anticancer mutual prodrugs. Chemical reduction of an aryl nitro trigger moiety was shown to initiate a spontaneous cyclisation/fragmentation reaction that simultaneously released the kinase inhibitor semaxanib (SU5416) and the amine- or alcohol-linked cytotoxin from the prodrugs. Preliminary cell testing and reduction potential measurements support optimisation of the compounds towards tumour-selective mutual prodrugs.

Authors


  •   Sansom, Geraud (external author)
  •   Kirk, Nicholas (external author)
  •   Guise, Christopher (external author)
  •   Anderson, Robert (external author)
  •   Smaill, Jeff (external author)
  •   Patterson, Adam (external author)
  •   Kelso, Michael J.

Publication Date


  • 2019

Citation


  • Sansom, G. N., Kirk, N. S., Guise, C. P., Anderson, R. F., Smaill, J. B., Patterson, A. V. & Kelso, M. J. (2019). Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study. Bioorganic and Medicinal Chemistry Letters, 29 (10), 1215-1219.

Scopus Eid


  • 2-s2.0-85062818694

Number Of Pages


  • 4

Start Page


  • 1215

End Page


  • 1219

Volume


  • 29

Issue


  • 10

Place Of Publication


  • United Kingdom

Abstract


  • Amide- and ester-linked kinase inhibitor-cytotoxin conjugates were rationally designed and synthesised as prototype hypoxia-activated anticancer mutual prodrugs. Chemical reduction of an aryl nitro trigger moiety was shown to initiate a spontaneous cyclisation/fragmentation reaction that simultaneously released the kinase inhibitor semaxanib (SU5416) and the amine- or alcohol-linked cytotoxin from the prodrugs. Preliminary cell testing and reduction potential measurements support optimisation of the compounds towards tumour-selective mutual prodrugs.

Authors


  •   Sansom, Geraud (external author)
  •   Kirk, Nicholas (external author)
  •   Guise, Christopher (external author)
  •   Anderson, Robert (external author)
  •   Smaill, Jeff (external author)
  •   Patterson, Adam (external author)
  •   Kelso, Michael J.

Publication Date


  • 2019

Citation


  • Sansom, G. N., Kirk, N. S., Guise, C. P., Anderson, R. F., Smaill, J. B., Patterson, A. V. & Kelso, M. J. (2019). Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study. Bioorganic and Medicinal Chemistry Letters, 29 (10), 1215-1219.

Scopus Eid


  • 2-s2.0-85062818694

Number Of Pages


  • 4

Start Page


  • 1215

End Page


  • 1219

Volume


  • 29

Issue


  • 10

Place Of Publication


  • United Kingdom