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

  • Bioorg Med Chem Lett. 2019 May 15;29(10):1215-1219. doi: 10.1016/j.bmcl.2019.03.015.
Geraud N Sansom  1 ,  Nicholas S Kirk  1 ,  Christopher P Guise  2 ,  Robert F Anderson  2 ,  Jeff B Smaill  2 ,  Adam V Patterson  2 ,  Michael J Kelso  3
Affiliations
  • 1. Molecular Horizons and School of Chemistry & Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Illawarra Health & Medical Research Institute, Wollongong, NSW 2522, Australia.
  • 2. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 3. Molecular Horizons and School of Chemistry & Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Illawarra Health & Medical Research Institute, Wollongong, NSW 2522, Australia. Electronic address: [email protected].
PMID: 30885680 DOI: 10.1016/j.bmcl.2019.03.015
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.

Keywords
4-Aminoaniline mustard; Anticancer; Bioreductive activation; Floxuridine; Hypoxia; Mutual prodrug; Semaxinib; Sunitinib.