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

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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.

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Funding sources

Funded in part by a Health Research Council of New Zealand grant 17/255 to Jeff Smaill and Adam Patterson and Australian National Health and Medical Research Council (NHMRC) Project Grant (APP1100432) to Michael Kelso.

Acknowledgment

We thank the University of Wollongong (Wollongong, Australia) and University of Auckland (Auckland, NZ) for supporting this work.

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