Swords, Bernadette; (1992) The synthesis of some novel phospholipid analogues as potential chemotherapeutic agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis is concerned with the synthesis of a range of novel phospholipid analogues with a variety of head groups and hydrocarbon chains. Three series of phospholipids consisting of the N-methyl, t-butyl and free amino head groups were prepared by a rapid three-step procedure involving phosphoramidite intermediates. The corresponding phosphitylating agents containing the amino group in a protected cyclic form were condensed with a variety of alcohols to yield cyclic phosphoramidites. The alcohols ranged from short to long alkyl chain primary, secondary and tertiary forms, including those containing a double bond and ester functionalities. The phosphites were then oxidised to the corresponding phosphates in high yield. Finally, P-N cleavage by simple hydrolyses with water gave the phospholipid analogues. A series of analogues with a serinol head group were prepared via phosphate methodology. Thus reaction of 2-amino-2-methyl-1,3- propanediol with alkyl phosphorodichloridates gave the corresponding cyclic phosphates. Subsequent hydrolyses yielded the desired serinol phospholipid analogues. An alternative route to the phospholipids via H-phosphonate methodology was pursued. Hydrolyses of cyclic phosphoramidites gave the H-phosphonate intermediates. However, subsequent attempts to oxidise and sulphurise the intermediates failed to yield the desired phospholipid analogues. The initial synthesis of a phosphitylating agent, where the oxygen had been replaced by a methylene was also pursued with some success. The biological evaluation of several of the novel phospholipid analogues as potential anti-HIV agents is reported.

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