The preparation of possible prodrugs for cancer chemotherapy
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
This thesis concerns the design and preparation of compounds which are relevant to a new strategy for the selective chemotherapeutic treatment of tumour cells. These bridged polycyclic compounds are prepared by Diels-Alder chemistry involving cyclic dienes. The bridge is to be cleaved at the cancer site by tumour-selective chemistry acting on an appropriate trigger. This activation of a low toxicity 'prodrug' results in the formation of a planar, aromatic structure which is a characteristic of known anti-cancer drugs (intercalating agents). The crucial step in the organic synthesis of these potential prodrugs is a DielsAlder reaction involving two classes of diene, 1-(methylthio)isobenzofurans and pyranones, with various dienophiles. Examination of this step started with the reaction of 1,1-bis(methylthio)ethene with various pyranones. Stable adducts were isolated from its reaction with methyl coumalate and a benzopyranone; but only substituted carbazoles were observed from the reaction with pyrano[3,4-b]indol-3-ones. An investigation into the thermal stability of the isolated adducts resulted in the observation of an unusual [1,]-methylthio migration. In comparison to 1, 1 bis(methylthio)ethene, 1-(methylthio)-1-(p-tolylsulfonyl)ethene was observed to have lower reactivity and regioselectivity upon reaction with electron-deficient pyranones. The resulting adducts were unstable due to the facile elimination of p-toluenesulfinic acid and only aromatic products were isolated. Diels-Alder adducts were isolated from the reaction of 1-(methylthio)-1-(p-tolylsulfonyl)ethene with 1-(methylthio)isobenzofurans, but they were of low stability and of mixed regio- and stereo- chemistries. The reaction of arynes with 1-(methylthio)isobenzofurans was also investigated. The Diels-Alder reaction between 3,4-didehydropyridine and a protected 1-(methylthio)isobenzofuran resulted in the preparation of a precursor of a tricyclic hetero-aromatic compound, namely the known biologically active compound, 2-azaanthraquinone.