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Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study |
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| Authors: | Geraud N Sansom Nicholas S Kirk Christopher P Guise Robert F Anderson Jeff B Smaill Adam V Patterson Michael J Kelso |
| Institution: | 1. Molecular Horizons and School of Chemistry & Molecular Bioscience, University of Wollongong, NSW 2522, Australia;2. Illawarra Health & Medical Research Institute, Wollongong, NSW 2522, Australia;3. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;4. The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand |
| 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: | Hypoxia Mutual prodrug Anticancer Bioreductive activation Sunitinib Semaxinib Floxuridine 4-Aminoaniline mustard |
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