Use this URL to cite or link to this record in EThOS:
Title: Design, synthesis and biological evaluation of novel antitumour compounds
Author: Kadri, Hachemi
ISNI:       0000 0004 2750 1868
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2010
Availability of Full Text:
Access from EThOS:
Access from Institution:
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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available