Curley, Duncan; (1992) Investigations and synthesis of some novel phosphate derivatives as potential anti-HIV agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The synthesis of a number of phosphoramidate derivatives of the anti-AIDS drug 3'-azido-3'-deoxythymidine (AZT) bearing an alkyl chain and a single N-linked, carboxyl-protected amino add has been described. The derivatives were found to possess potent activity against the established etiologic agent for the disease, the Human Immunodefidency Virus (HIV). A high-yielding method for the preparation of the synthetic precursors to these phosphoramidate derivatives - the alkyl amino acyl phosphorochloridates - has been developed. The mechanism of action of the phosphoramidate derivatives was probed by the synthesis of a series of compounds in which the distance between the amino add carboxyl moiety and the phosphoramidate bond was varied. Activity was found to decrease on increasing the length of the methylene spacer. This is consistent with a mechanism of action involving cleavage of the phosphoramidate bond. Further investigations revealed that an L-amino acid is not required for activity. Incubation of one of the phosphoramidate compounds with HFV-1 protease revealed very little decomposition. These findings seem to preclude HIV-specific activation of the compounds. However, investigation of the stability of the derivatives in aqueous media showed them to be resilient to chemical hydrolysis over a period of about five days, suggesting that other mechanisms may play a role in the activation of these compounds. Various unsuccessful attempts were made to conjugate a dipeptide to a nucleoside via a phosphoramidate linkage. Variations in the nucleoside moiety of the phosphoramidate compounds were also explored. It appears that a bioactive nucleoside is not a prerequisite for activity, thus illustrating the potential utility of the phosphoramidate approach in conferring activity on nucleoside analogues hitherto considered ineffective against HIV. A Table of the phosphoramidate derivatives prepared and the results of their biological evaluation against HFV-1 in vitro can be found on page 226.

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