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Design, synthesis and biological evaluation of novel antitumour compounds

Kadri, Hachemi 2010. Design, synthesis and biological evaluation of novel antitumour compounds. PhD Thesis, Cardiff University.

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Cancer is a leading cause of death worldwide. Chemotherapy is the main approach used currently for the treatment and management of this disease especially disseminated malignant tumours. Traditional anticancer drugs have a limited selectivity as they target mainly DNA synthesis or cell proliferation leading to severe side effects. However, the newer anti-cancer drugs are more selective in targeting certain aberrant signalling pathways in cancer cells. In the first part of this work, a series of benzimidazole and indole analogues of a potent antitumour benzothiazole lead compound were synthesised to enhance its pharmaceutical properties. Their antitumour activity was tested against different human cancer cell lines. In most cases, these analogues did not display any significant activity except for some of the N-substituted ones with Moluenesulfonyl group, which yielded submicromolar GI50 values. The second part of the work focuses on the design and synthesis of antitumour agents targeting the Wnt signalling pathway. The aberrant activation of this signalling pathway has been implicated in a wide spectrum of cancers. Disheveled PDZ domain is an essential protein-protein interaction mediator in the Wnt signalling pathway. Novel antitumour agents were designed using molecular modelling approaches to selectively inhibit the PDZ domain and hence abolish tumouregenic effects associated with the aberrant activation of Wnt signalling. Biochemical binding assays showed that one of the hits obtained through high-throughput docking binds specifically to the Disheveled PDZ domain. Structural optimisation studies of this hit were also carried out in order to improve activity.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
ISBN: 9781303195525
Funders: Government of Algeria, British Association for Cancer Research
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:29

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