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

Authors

Geraud Sansom, University of WollongongFollow
Nicholas Kirk, University of WollongongFollow
Christopher Guise, University of Auckland
Robert Anderson, University of Auckland
Jeff Smaill, University of Auckland
Adam Patterson, University of Auckland
Michael J. Kelso, University of WollongongFollow

RIS ID

134177

Publication Details

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.

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.

Grant Number

NHMRC/1100432