Narashiman, Padma Rani; (1993) The synthesis of some novel phosphoramidates of chemotherapeutic interest. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The human immunodeficiency virus (HTV) is known to be the causative agent of the acquired immunodeficiency syndrome (AIDS) and the most promising chemotherapeutic strategy used in combating this virus is to use inhibitors of HIV replication. At present nucleoside analogues are some of the most promising anti-HTV agents known. However, they suffer from a number of limitations. One new class of compounds which may play an important role in AIDS therapy is the alkylating agents. The design and synthesis of these agents as potential anti-HTV drugs is the subject of the first part of this thesis. The synthesis of a variety of phosphoramidate derivatives of nitrogen mustard is described, along with the results of the biological evaluation of some of these agents against HTV. It is thought that these agents may act as inhibitors of HTV DNA and/or RNA replication. Their potential antineoplastic activity is also considered. The synthesis of some alkyl and trihaloalkyl phosphoramidate derivatives of nitrogen mustard from N,N-bis(2-chloroethyl)amino (alkyl or trihaloalkyl) phosphorochloridate and various carboxy protected amino acids is described along with a discussion of the in vitro anti-HTV test results of some of these agents. The next series of derivatives was designed with the aim of making it more lipophilic as it was thought that this property could be a contributory factor in the activity against the virus. Carboxy protected amino acids of varying degrees of lipophilicity were incorporated in 4-substituted phenyl phosphoramidate derivatives of nitrogen mustard. Some peptide derivatives were also synthesised and tested for potential anti-HTV activity. The subject of the second part of this thesis was to investigate the synthesis of some analogues of cyclophosphamide, the most widely used alkylating agent in cancer chemotherapy. Acrolein, a metabolite of cyclophosphamide is thought to be responsible for the cause of haemorrhagic cystitis which can be a fatal condition. It was attempted to prepare 5-hydroxycyclophosphamide, a 6-membered ring derivative, in the hope that it would overcome the toxicity associated with the release of acrolein. However, it was possible to only isolate the alternative 5-membered ring analogue from reactions of dichlorophosphoramide with aminopropan-2,3-diol. The synthesis of 2-bis(2-chloroethyl)amino-l,3,2-oxaza, 2-bis(2-chloroethyl)amino-5- hydroxymethyl-1,3,2-dioxa and 2-bis(2-chloroethyl)amino-5-acetyloxymethyl-1,3,2- oxazaphosphacyclopentane 2-oxide to establish the nature of the isolated 5-membered ring analogue is described along with attempts to find alternative routes to 5-hydroxy cyclophosphamide. Attempts were also made to prepare 5-O-allyl cyclophosphamide and some phosphite derivatives.

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