Organophosphorus Chemistry: Therapeutic Intervention in Mechanisms of Viral and Cellular Replication

Nick   J.   Wardle; S.   W. A.   Bligh; Harry   R.   Hudson

doi:10.2174/138527205774913123

Abstract

Literature publications (up to September 2004) concerning the targeted intervention of organophosphorus synthons in mechanisms of the replicative cycle, and the therapeutic benefits resulting (of particular relevance to anticancer and antiviral therapeutics) are reviewed. DNA-cross-linking agents comprising established oxazaphosphorinanes such as cyclophosphamide, ifosfamide and trofosfamide, and the aziridine agent thiotepa are discussed along with recent developments in prodrugs of associated activated metabolites. Established and novel nucleoside phosphonates are described subsequently in relation to inhibition of viral and cellular DNA polymerases and reverse transcriptases, along with inhibition of nucleotide metabolising enzymes such as purine nucleoside phosphorylase, thymidine phosphorylase, inosine monophosphate dehydrogenase, S-adenosyl-L-homocysteine hydrolase, and ribonucleoside diphosphate reductase. In this context, the role of organophosphorus chemistry in the development of intracellular delivery systems for antiviral/anticancer nucleotides has been reviewed, as have therapeutic developments concerning the pyrophosphate mimetic foscarnet. Finally, the inhibition of virally-encoded proteases such as HIV-PR, HCMV-PR and HCV NS3/NS4A protease by substrate-mimetic organophosphorus synthons has been discussed along with the role of synthetic oligonucleotides in antisense therapies for a range of disease-states.

Keywords: Antiproliferative agents, nephrotoxicities, breast cancer xenograft models, Aziridines, DNA replication, CYP-450, Immunomodulation

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