Show simple item record

dc.contributor.authorLo, Anthony Tin Shing
dc.date.accessioned2014-12-14T23:36:24Z
dc.date.available2014-12-14T23:36:24Z
dc.date.issued2014-07-17
dc.identifier.urihttp://hdl.handle.net/2123/12469
dc.description.abstractA set of aminoalkylamine substituted anthraquinones (AAQs) was successfully synthesised by aminating 1- or 1,5-chloroanthraquinones in a single reaction step. These substituted anthraquinones, 1C3 or 1,5C3, were tethered to minor groove binding polyamides with between 1 - 3 N-methyl pyrrole units (Py) to produce a library of Py-AAQ compounds. It was envisaged that these compounds could improve cytotoxicity through bimodal damage to DNA relative to the individual polyamide or AAQ moieties. A set of py-AAQ platinum complexes was also successfully synthesised by a platinum-mediated alkylamine to nitrile addition. The additional conjugation of a platinum nitrile complex to Py-AAQ conjugates was predicted to generate agents that are more cytotoxic than the Py-AAQ conjugates by damaging DNA via a minor groove binding (MGB)-intercalation-platination mechanism. All newly synthesised Py-AAQs and associated imino coordinated platinum(II) complexes were examined for cytotoxic activity in DLD-1 colon and MDA-MB-231 breast carcinoma cells using MTT assays. Tethering polyamides to AAQs was found to diminish the activity of the anthraquinones, while the platinum(II) conjugates exhibited moderate cytotoxicity in both carcinoma cell lines (IC50 16–30 µM). Subcellular distribution studies showed that the inactive Py-AAQ compounds tended to be localised in the lysosomes or pinocytic vesicles. Three-dimensional spheroid tumour penetration studies showed that Py-AAQ conjugates can be taken up slowly by cells enabling deeper penetration (60-100 µm) into the tumour than either of the individual 1C3 or 1,5C3 moieties (20-30 µm). Subcellular distribution studies indicated that the platinum(II) conjugates were localised in the nucleoli. The 1C3 tethered platinum complexes were found to have a binding specificity of 3’-(A/T)GTA-5’ nucleotide sequence using a polymerase stop assay whereas the 1-3py-1,5C3 tethered platinum complexes were found to have a similar binding specificity as cisplatin.en_AU
dc.publisherUniversity of Sydneyen_AU
dc.publisherFaculty of Scienceen_AU
dc.publisherSchool of Chemistryen_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectAnthraquinoneen_AU
dc.subjectAnti-tumouren_AU
dc.subjectPlatinum complexesen_AU
dc.subjectPolyamideen_AU
dc.subjectOcta-arginineen_AU
dc.titleNovel polyamide amidine anthraquinone platinum(II) complexes for enhancing DNA binding and tumour penetrationen_AU
dc.typePhD Doctorateen_AU
dc.date.valid2014en_AU
dc.type.pubtypeDoctor of Philosophy Ph.D.en_AU
dc.description.disclaimerAccess is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.en_AU


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record