Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors.

Show simple item record Dickson, Benjamin en Wong, Winifred en Wilson, William en Hay, Michael en 2019-05-28T21:33:54Z en 2019-04-19 en
dc.identifier.citation Molecules 24(8) 19 Apr 2019 en
dc.identifier.issn 1420-3049 en
dc.identifier.uri en
dc.description.abstract Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible "trigger" to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration. en
dc.format.medium Electronic en
dc.language eng en
dc.relation.ispartofseries Molecules (Basel, Switzerland) en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.rights.uri en
dc.subject Quinazolines en
dc.subject Antineoplastic Agents en
dc.subject Prodrugs en
dc.subject Chromatography, Liquid en
dc.subject Magnetic Resonance Spectroscopy en
dc.subject Mass Spectrometry en
dc.subject Poly(ADP-ribose) Polymerase Inhibitors en
dc.title Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors. en
dc.type Journal Article en
dc.identifier.doi 10.3390/molecules24081559 en
pubs.issue 8 en
pubs.volume 24 en
dc.rights.holder Copyright: The authors en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.subtype research-article en
pubs.subtype Journal Article en
pubs.elements-id 769954 en Medical and Health Sciences en Medical Sciences en Anatomy and Medical Imaging en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1420-3049 en
pubs.record-created-at-source-date 2019-04-24 en
pubs.dimensions-id 31010230 en

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