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UBC Theses and Dissertations

Isolation, structure determination and total synthesis of potential cancer chemotherapeutic agents from natural sources Britton, Robert A.


The ultimate goal in the chemotherapeutic treatment of cancer is the development of drugs that are highly effective against tumor cells and have little or no effect on healthy cells. Key to this pursuit is the identification of differences that exist between the life cycle of normal and cancerous cells. Thus, the discovery of new small molecule inhibitors of enzymes that regulate cellular growth and division should provide a better understanding of these biological processes and perhaps lead to more selective cancer treatments. Mitosis, or cell division, is disrupted by antimitotic agents, which correspondingly have become the most promising chemotherapeutics in cancer treatment. Recently, the Caribbean soft coral Erythropodium caribaeorum was shown to be a good source of eleutherobin, a potent antimitotic agent. Having procured eleutherobin from this source, synthetic manipulations of the natural material provided a series of eleuthoside congeners, which were assayed for antimitotic activity. A remarkable relationship between the Δ[sup 2’,3’] olefin and eleuthoside biological activity was highlighted by these studies. The G2 checkpoint is one of a series of checkpoints that temporarily halt cell cycle progression in order to allow for repair of damaged DNA. It has been demonstrated in vitro that the inhibition of this checkpoint, in combination with a DNA damaging agent, selectively potentiates the killing of cancer cells. Extracts of the Brazilian ascidian Didemnum granulatum demonstrated G2 checkpoint inhibition activity. Fractionation of these extracts resulted in the isolation of isogranulatimide. In order to unambiguously confirm the structural assignment of this substance, generate sufficient material for biological testing and investigate the effect of structure on its biological activity, an efficient synthesis of isogranulatimide and several congeners was developed. Concurrently, two new analogues of okadaic acid, a potent protein phosphatase inhibitor, have been isolated from the sponge Merriamum oxeato, collected in Jervis Inlet, British Columbia. These substances displayed pronounced G2 checkpoint inhibition activity and represent the first examples of diarrhetic shellfish poisons (DSP) in the Northeastern Pacific Ocean. A total synthesis of 13-methoxy-15-oxozoapatlin, a G2 checkpoint inhibitor and antimitotic agent, has also been completed. Employing a linear sequence of 22 synthetic transformations, a renewable source of this structurally complex pentacyclic diterpene has been realized. The completion of this synthesis relied on the development of new synthetic methods useful in the construction of bicyclo[3.2.1 ]octanes.

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