Shackleton, Janice Mary; (1993) Synthesis and biological evaluation of some novel phosphate derivatives of the anti-viral drug araA. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The nucleoside analogue 9-β-D-arabinofuranosyladenine (araA) has found widespread use as an anti-viral drug in the treatment of various herpesvirus infections. AraA suffers from a number of limitations, most importantly a low activity due to enzymatic deamination in the body by adenosine deaminase and, along with most nucleoside analogues, a dependence on enzymatic phosphorylation by cellular kinases to the active 5'-phosphate form(s). Other disadvantages include a low aqueous solubility, a low lipophilicity and a moderate toxicity. The research presented in this thesis investigates the synthesis of some novel 5'-phosphate derivatives of araA as potential uncharged, membrane-soluble, deamination-resistant pro-drugs of ara-5'-monophosphate (araAMP). Generally, the method involved the preparation of the appropriate phosphorylating agent and its subsequent reaction with unprotected araA. The biological activity of these derivatives was evaluated by determining their ability to inhibit the synthesis of DNA in vitro using a tritiated thymidine incorporation assay employing mammalian epithelial cells. Firstly, the 5'-bis(2-fluoroethyl) and 5'-bis(2-bromoethyl) phosphate triesters of araA were synthesized. Preparation of araA-5 '-bis(2-iodoethyl) phosphate was subsequently attempted by the reaction of the 5' -bis(2-bromoethyl) derivative with potassium iodide in acetone. The synthesis of a number of mixed, unsymmetrical 5'-phosphate derivatives of araA was investigated. A series of 5'-alkyl (2,2,2-trichloroethyl) phosphate triesters of araA were prepared by the method outlined above and additionally, in the case of araA-5'-butyl (2,2,2-trichloroethyl) phosphate, by a transesterification reaction. The synthesis of araA-5'-ethyl phenyl phosphate, araA-5' -(2,2,2-trichloroethyl) phenyl phosphate and some 5' -(2,2,2-trichloroethyl)para-substituted phenyl derivatives was carried out. A series of 5'-ethyl (benzyl-protected glycolyl) phosphate triesters of araA were also prepared. Hydrogenolysis of these derivatives gave the required deprotected products. AraA-5'-(2,2,2-trichloroethyl) (8-benzyloxy-3,6-dioxaoctyl) phosphate was synthesized and its hydrogenolysis was attempted. The results of in vitro biological testing of these mixed, unsymmetrical derivatives are discussed. The mechanism by which these 5' -phosphate triesters of araA exert their biological effects probably involves the hydrolysis of the phosphate moiety to yield either the 5'-monophosphate (araAMP) or the parent nucleoside (araA). The in vitro biological activity of two 5'-phosphate triesters of araA was compared with their analogous 5'-phosphinate esters to help elucidate the matter. The results of the assay were indicative of a mode of action largely involving the release of araAMP and also to a minor extent araA. Finally, the susceptibility to chemical hydrolysis of the 5'-bis(2,2,2-trifluoroethyl), 5'-bis(2,2,2-trichloroethyl) and 5'-butyl (2,2,2-trichloroethyl) phosphate triesters of araA was investigated and attempts to purify and characterize the resulting products were carried out.

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