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Title: Design, synthesis and biological evaluation of narciclasine analogues
Author: Griffiths, Natalie Jane
ISNI:       0000 0004 5923 4055
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2015
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Whilst the cultivation of the Amaryllidaceae genus has primarily been for their ornamental properties, their use in traditional medicine is also well documented. Although over 100 alkaloids from this genus have been isolated, the phenanthridinone analogues narciclasine and pancratistatin isolated from the daffodil bulb, are particularly interesting due to their cytostatic and cytotoxic properties. They have potent and selective anticancer activity which is seemingly unique when compared to currently available chemotherapeutic agents. However, they have yet to be fully exploited as therapeutic agents due to their complex total synthesis and scarce availability from natural sources. The work described herein demonstrates short synthetic sequences which have been developed to gain simple analogues of these natural products. These have been assessed by MTS cell proliferation assays in order to gain more understanding of the SARs of narciclasine and pancratistatin, which in turn will be used to design additional biologically active compounds. These natural products share a dihydroisoquinolinone core and a series of AB-ring analogues were synthesised using a one-pot procedure previously developed and published by the group. Analogues were tested for anticancer activity by MTS cell proliferation assays against HT29 colon cancer cell line. Although these analogues were not biologically active their isoquinolinone counterparts showed a marked improvement with IC50 values below 300 μM. Functionalisation to simulate the C-ring of the natural products had limited success. Allylation gave analogues with IC50 values below 250 μM, however attempts at subsequent dihydroxylation proved to be capricious. Acetylation at the benzylic position showed some potential with the most promising compound having an IC50 value of 33 μM. Upon N-methylation of the acetylated lactam some activity was lost with the IC50 value increasing to 110 μM. Optimisation of preliminary investigations was undertaken in order to synthesise late stage ABCring analogues using Robinson annulation, Curtius rearrangement and Friedel-Craft acylation as key reaction steps. A novel methylenedioxy analogue was synthesised and further functionalisation was briefly explored with very limited success. Preliminary in-house MTS cell proliferation assays against the HT29 cells showed promising biological activity with IC50 values ranging from 9 to 50 μM. These selected analogues were sent to the NCI for further analysis. In order to improve the water solubility of the natural product a quinazolinone AB-ring core was incorporated to generate late stage tricyclic analogues with a basic nitrogen. This utilised a onestep synthesis from anthranilamide and glutaraldehyde starting materials. Unfortunately these compounds were found to be unstable and further functionalisation was problematic due to decomposition of the tricyclic compounds. C-ring analogues were also examined which were derived from sugars such as L- and D-lyxose, furnishing hydroxylated derivatives with known absolute and relative stereochemistry.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available