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

Geraud N Sansom; Nicholas S Kirk; Christopher P Guise; Robert F Anderson; Jeff B Smaill; Adam V Patterson; Michael J Kelso

doi:10.1016/j.bmcl.2019.03.015

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. Epub 2019 Mar 13.

Authors

Geraud N Sansom¹, Nicholas S Kirk¹, Christopher P Guise², Robert F Anderson², Jeff B Smaill², Adam V Patterson², Michael J Kelso³

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: mkelso@uow.edu.au.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alcohols / chemistry
Amines / chemistry
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation
Cytotoxins / chemistry*
Cytotoxins / pharmacology
Drug Screening Assays, Antitumor / methods
Floxuridine / chemistry
Humans
Indoles / chemistry
Indoles / pharmacology
Molecular Structure
Prodrugs / chemical synthesis*
Prodrugs / pharmacology
Proof of Concept Study
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Pyrroles / chemistry
Pyrroles / pharmacology
Structure-Activity Relationship
Tumor Hypoxia

Substances

Alcohols
Amines
Antineoplastic Agents
Cytotoxins
Indoles
Prodrugs
Protein Kinase Inhibitors
Pyrroles
Floxuridine
Semaxinib