Synthesis and Investigation of Anti-proliferative Thieno[2,3-b]pyridine Derivatives with Enhanced Solubility

ResearchSpace Repository

Show simple item record

dc.contributor.advisor Barker, D en
dc.contributor.author Haverkate, Natalie en
dc.date.accessioned 2017-06-30T00:03:00Z en
dc.date.issued 2017 en
dc.identifier.uri http://hdl.handle.net/2292/33888 en
dc.description Full text is available to authenticated members of The University of Auckland only. en
dc.description.abstract Phospholipases are important regulators of cellular processes, in particular the PLC-δ (phospholipase C-delta) isoform has been identified as being involved in cellular processes directly involved in cancer progression. Therefore, the design of compounds to inhibit PLC-δ has become a viable target for anticancer therapy. A number of compounds have been identified within the thienopyridine family that have shown good anti-proliferative activity in cancer cell lines HCT-116 and MDA-MB-231, but their practicality as potential drugs is limited by their poor solubility. The aim of this project was to prepare novel analogues of thienopyridines that contain the known successful characteristics of the previous compounds and introduce new functional groups that would improve the solubility, all whilst maintaining good anti-proliferative activity. Seven different series of thieno[2,3-b]pyridine derivatives were synthesised; the pyrrolo[2,3- b]quinolones, 5-acetyl-6-methylthieno[2,3-b]pyridines, 5-(1-hydroxyethyl)-6- methylthieno[2,3-b]pyridines, N-benzyl thieno[2,3-b]naphthyridines, N-methyl thieno[2,3- b]naphthyridines, pyrano[4,3-b]thieno[3,2-e]pyridines and other thieno[2,3-b]pyridine derivatives to give a total of 49 new analogues. The compounds were then examined using molecular modelling docking studies, followed by biological testing at the Auckland Cancer Society Research Centre (ACSRC) and the National Cancer Institute (NCI). These studies enabled comparisons between the modelling scores and their biological activity to be made. This allowed for an improved structure-activity relationship (SAR) in this family of compounds, introducing descriptors allowing improved solubility. A number of highly bioactive compounds were discovered that, additionally, had improved solubility compared to previous analogues, specifically compounds 19b and 19e. These compounds had IC50 values in the low nanomolar range - the lowest recorded for the known thienopyridine derivatives. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof Masters Thesis - University of Auckland en
dc.relation.isreferencedby UoA99264918811402091 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 Restricted Item. Available to authenticated members of The University of Auckland. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.rights.uri http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ en
dc.title Synthesis and Investigation of Anti-proliferative Thieno[2,3-b]pyridine Derivatives with Enhanced Solubility en
dc.type Thesis en
thesis.degree.discipline Chemistry en
thesis.degree.grantor The University of Auckland en
thesis.degree.level Masters en
dc.rights.holder Copyright: The author en
pubs.elements-id 633612 en
pubs.record-created-at-source-date 2017-06-30 en


Files in this item

Find Full text

This item appears in the following Collection(s)

Show simple item record

http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/3.0/nz/

Share

Search ResearchSpace


Advanced Search

Browse

Statistics