Jones, Brian Colin Nicholas Morgan; (1991) Design, synthesis and biological evaluation of some novel anti-cancer and anti-HIV chemotherapeutic agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The work presented in this thesis has been directed towards the synthesis of uncharged, masked phosphate derivatives of the anti-cancer nucleoside analogue araC, the anti-HIV nucleoside analogue AZT and some other modified nucleosides which are of biological interest, that is, 3'-fluoro-3'-deoxythymidine, 3'-iodo-3'-deoxythymidine and 3'-acetylthymidine. It was hoped that this approach would achieve cellular penetration while overcoming some of the mechanisms of resistance to treatment which are observed for the parent nucleosides. The first chapter, the review, presents the background data and knowledge pertaining to cancer (especially leukaemia) and to the acquired immunodeficiency syndrome. The chemistry and biology of the compounds employed, along with related compounds are described. In chapter two, the synthesis of symmetric 5'-dialkyl phosphate triester derivatives of araC is described, along with a lipophilicity study and biological testing in mammalian epithelial cells. The compounds showed interesting activity which correlated with increasing lipophilicity. An attempted X-ray crystallographic study of l-p-D-arabinofuranosylcytosine-5'-diethyl phosphate is also presented. In the third chapter, the synthesis of asymmetric 5'-dialkyl phosphate triester, phosphoramidate and phosphorodiamidate derivatives of araC are described. The results of biological testing in mammalian epithelial cells are discussed. The attempted combination of the active moiety of the alkylating agent cyclophosphamide with araC is described. The reason why protection of araC may be necessary is outlined and a novel base protected derivative of araC is presented. A Nuclear Overhauser Experiment is corelated with molecular graphics results in order to assign stereochemistry to the separated diasteroisomers of 1-β-D-arabinofuranosylcytosine-5'-ethyl-2,2,2-trichloroethyl phosphate. The fourth chapter describes the syntheses of AZT, 3'-iodo-3'- deoxythymidine and 3'-acetylthymidine and the subsequent use of a modified Yoshikawa reaction to the production of phosphorodiamidate derivatives of the aforementioned nucleoside analogues and of 3'-fluoro-3'-deoxythymidine. In-vitro anti-HIV biological testing was carried out on the AZT phosphorodiamidates. As the method by which the active AZT phosphorodiamidates act as inhibitors of HIV probably involves the hydrolyses of the phosphate moiety to either the 5'-monophosphate or the parent nucleoside, some studies on the hydrolysis of four of the analogues in the AZT series were carried out in human plasma.

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