Design, Synthesis and Biological Evaluation of Narciclasine Analogues

  • Natalie Griffiths

Student thesis: Doctoral ThesisPhD


Whilst the cultivation of the Amaryllidaceae genus has primarily been for their ornamentalproperties, their use in traditional medicine is also well documented. Although over 100 alkaloidsfrom this genus have been isolated, the phenanthridinone analogues narciclasine andpancratistatin isolated from the daffodil bulb, are particularly interesting due to their cytostatic andcytotoxic properties. They have potent and selective anticancer activity which is seemingly uniquewhen compared to currently available chemotherapeutic agents. However, they have yet to be fullyexploited as therapeutic agents due to their complex total synthesis and scarce availability fromnatural sources. The work described herein demonstrates short synthetic sequences which havebeen developed to gain simple analogues of these natural products. These have been assessed byMTS cell proliferation assays in order to gain more understanding of the SARs of narciclasine andpancratistatin, 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 weresynthesised 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 coloncancer cell line. Although these analogues were not biologically active their isoquinolinonecounterparts showed a marked improvement with IC50 values below 300 μM. Functionalisation tosimulate the C-ring of the natural products had limited success. Allylation gave analogues with IC50values below 250 μM, however attempts at subsequent dihydroxylation proved to be capricious.Acetylation at the benzylic position showed some potential with the most promising compoundhaving an IC50 value of 33 μM. Upon N-methylation of the acetylated lactam some activity was lostwith the IC50 value increasing to 110 μM.Optimisation of preliminary investigations was undertaken in order to synthesise late stage ABCringanalogues using Robinson annulation, Curtius rearrangement and Friedel-Craft acylation as keyreaction steps. A novel methylenedioxy analogue was synthesised and further functionalisation wasbriefly explored with very limited success. Preliminary in-house MTS cell proliferation assays againstthe HT29 cells showed promising biological activity with IC50 values ranging from 9 to 50 μM. Theseselected 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 wasincorporated to generate late stage tricyclic analogues with a basic nitrogen. This utilised a onestepsynthesis from anthranilamide and glutaraldehyde starting materials. Unfortunately thesecompounds were found to be unstable and further functionalisation was problematic due todecomposition of the tricyclic compounds. C-ring analogues were also examined which werederived from sugars such as L- and D-lyxose, furnishing hydroxylated derivatives with knownabsolute and relative stereochemistry.
Date of Award29 Sept 2015
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorLorenzo Caggiano (Supervisor)


  • narciclasine
  • pancratistatin
  • Amaryllidaceae
  • isocarbostyril
  • phenanthridinone

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