Publication:
Investigations into the synthesis, DNA-binding and efficacy of novel phenazine-1,6-carboxamides as potential anti-cancer drug candidates

dc.contributor.advisor Ball, Graham en_US
dc.contributor.advisor Hunter, Luke en_US
dc.contributor.advisor Wakelin, Laurence en_US
dc.contributor.author Jung, Jane en_US
dc.date.accessioned 2022-03-15T08:54:12Z
dc.date.available 2022-03-15T08:54:12Z
dc.date.issued 2021 en_US
dc.description.abstract Bifunctional nitrogen mustards form DNA inter-strand crosslinks and are clinically important due to their broad-spectrum anti-tumour activity. However, the crosslinks are readily repaired by cancer cells, leading to fatal drug resistance, and their tendency to form monofunctional adducts exacerbates their carcinogenicity and mutagenicity. Equipping planar aromatic chromophores with alkylating groups to direct the alkylation of DNA by intercalation enhances alkylation efficacy, cytotoxicity, and modulates adduct specificity. Therefore, a N1,N6-bis(2-(aziridin-1-yl)ethyl)phenazine-1,6-dicarboxamide molecule named “Phenazir” was designed that bears aziridine groups at positions on the chromophore that predisposes them to nucleophilic attack by a guanine and adenine in the major and minor groove, respectively. It was anticipated that the resultant novel crosslinks would be difficult for cancer cells to repair, and therefore, Phenazir would be less susceptible to the development of resistance in a clinical setting. This thesis investigates the synthesis and biological activity of Phenazir and its analogues, and its binding to DNA through spectroscopic methods. Phenazir and its analogues were successfully synthesised and cytotoxicity measurements revealed that Phenazir had IC50 concentrations in the 5 to 25 nM range, and that it caused extensive DNA double strand breaks. Cytotoxicity measurements of other analogues, with different linker lengths and substitutions of the phenazine core, resulted in up to a 30-fold increase in activity. UV-Vis experiments demonstrated that the phenazine-1,6-carboxamide scaffold intercalated and alkylated DNA under mild conditions. NMR experiments were unsuccessful in obtaining solution structures of a Phenazir-oligomer complex, likely hindered by aggregation or polymerisation of Phenazir at high concentrations. However, molecular dynamics studies suggest that the aziridines in intercalated Phenazir are appropriately located to promote DNA alkylation. MALDI and nanoESI-MS were used to identify the alkylated adducts formed upon complexing a 5’ – TpG – 3’-containing oligomer with Phenazir, demonstrating that Phenazir alkylates efficiently at the TpG step with some evidence of interstrand crosslinking. Overall, the work in this thesis has led to the development of phenazine-1,6-carboxamides as a new class of highly active, DNA-targeting cytotoxic molecules that explore the previously untapped potential of threading bis-alkylation as a drug design approach. en_US
dc.identifier.uri http://hdl.handle.net/1959.4/71221
dc.language English
dc.language.iso EN en_US
dc.publisher UNSW, Sydney en_US
dc.rights CC BY-NC-ND 3.0 en_US
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/3.0/au/ en_US
dc.subject.other Anti-cancer en_US
dc.subject.other DNA en_US
dc.subject.other Alkylating drugs en_US
dc.title Investigations into the synthesis, DNA-binding and efficacy of novel phenazine-1,6-carboxamides as potential anti-cancer drug candidates en_US
dc.type Thesis en_US
dcterms.accessRights embargoed access
dcterms.rightsHolder Jung, Jane
dspace.entity.type Publication en_US
unsw.accessRights.uri http://purl.org/coar/access_right/c_f1cf
unsw.date.embargo 2024-06-15
unsw.description.embargoNote Embargoed until 2024-06-15
unsw.identifier.doi https://doi.org/10.26190/unsworks/2394
unsw.relation.faculty Science
unsw.relation.originalPublicationAffiliation Jung, Jane, School of Chemistry, Science, UNSW en_US
unsw.relation.originalPublicationAffiliation Ball, Graham, School of Chemistry, Science, UNSW en_US
unsw.relation.originalPublicationAffiliation Hunter, Luke, School of Chemistry, Science, UNSW en_US
unsw.relation.originalPublicationAffiliation Wakelin, Laurence, School of Chemistry, Science, UNSW en_US
unsw.relation.school School of Chemistry *
unsw.thesis.degreetype PhD Doctorate en_US
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