Synthetic studies on a potential antitumour compound
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Mycalamides A and B, isolated recently from a marine sponge of the genus Mycale, show strong in vitro and in vivo antiviral and antitumour properties. In this research, the chemistry of the mycalamides was explored and structure-activity relationships were determined, with the overall objective of producing analogues with better, or more selective biological activities. Along with this, the conformational behaviour of the mycalamides and a related compound, pederin, was examined. Simple esters, silyl and alkyl ethers of the hydroxyl and amide functionalities were prepared during initial studies. While many of these proved to be inactive, they were still useful as protected intermediates for use in acid and base catalysed hydrolysis reactions. In the course of the acid catalysed reactions, the acetal groups were partially or completely hydrolysed, eliminated, or exchanged and cleavage fragments were isolated. The exocyclic double bond was hydrogenated, epoxidised and rearranged in further studies. Base catalysed hydrolysis, elimination and rearrangement reactions were examined extensively and many interesting and unexpected products were obtained, including epimers and further cleavage fragments. Reduction and oxidation reactions also provided a source of important and potentially useful derivatives. In all, more than one hundred and ten derivatives of mycalamides A and B were prepared, characterised and tested for biological activity. The central portion of the structure, including the a-hydroxy amide and neighbouring groups, was shown to be crucial for the biological activity. A simple model structure was prepared containing some of these elements. The structure-activity relationships described in this work, combined with a better knowledge of the chemistry and conformational behaviour of these compounds, should together provide renewed stimulus for the ongoing study and development of these potential antitumour compounds.