Marked Inhibitory Activity of Masked Aryloxy Aminoacyl Phosphoramidate Derivatives of Dideoxynucleoside Analogues Against Visna Virus Infection
- 1 April 1998
- journal article
- research article
- Published by Wolters Kluwer Health in JAIDS Journal of Acquired Immune Deficiency Syndromes
- Vol. 17 (4) , 296-302
- https://doi.org/10.1097/00042560-199804010-00002
Abstract
Lipophilic masked aryloxyaminoacylphosphoramidate derivatives of 2′,3′-dideoxynucleoside (ddN) analogues with potent anti-HIV activity (i.e., stavudine [d4T], azidothymidine [AZT], dideoxycytidine [ddC], 3′thio-2′,3′-dideoxy cytidine [3TC], dideoxyadenosine [ddA], and 2′,3′-didehydro-2′,3′-dideoxyadenosine [d4A]) activity were evaluated for their activity against visna virus (VV) in sheep choroid plexus (SCP) cells. The activity of several prodrug derivatives against VV proved markedly superior to that of the corresponding free ddN analogues. In particular, the d4A and ddA prodrug derivatives were exquisitely inhibitory in this model system (50% effective concentration [EC50], ≤0.003 μM), and their anti-VV potency exceeded by at least 200-fold the antiviral potency of the corresponding free nucleosides. Marked differences were noted in the anti-VV potencies of several of the test compounds depending on the nature of the amino acid linked to the 5′-phosphate moiety, the nature of the nucleoside, or both. In view of the stability of the prodrugs in lamb serum, the VV infection model in lambs may be considered highly useful for investigating the in vivo antiretroviral efficacy of these type of drugs, particularly the d4T, ddA, and d4A prodrug derivatives.Keywords
This publication has 18 references indexed in Scilit:
- Conversion of 2′,3′-dideoxyadenosine (ddA) and 2′,3′-didehydro-2′,3′-dideoxyadenosine (d4A) to their corresponding aryloxyphosphoramidate derivatives markedly potentiates their activity against human immunodeficiency virus and hepatitis B virusFEBS Letters, 1997
- Cyclic saligenyl phosphotriesters of 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T) — a new pro-nucleotide approachBioorganic & Medicinal Chemistry Letters, 1997
- Anti-HIV and Anti-HBV Activity and Resistance Profile of 2′,3′-Dideoxy-3′-Thiacytidine (3TC) and Its Arylphosphoramidate Derivative CF 1109Biochemical and Biophysical Research Communications, 1996
- Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.Proceedings of the National Academy of Sciences, 1996
- Decomposition Pathways and in Vitro HIV Inhibitory Effects of IsoddA Pronucleotides: Toward a Rational Approach for Intracellular Delivery of Nucleoside 5‘-MonophosphatesJournal of Medicinal Chemistry, 1996
- Aryl Phosphoramidate Derivatives of d4T Have Improved Anti-HIV Efficacy in Tissue Culture and May Act by the Generation of a Novel Intracellular MetaboliteJournal of Medicinal Chemistry, 1996
- Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivativesInternational Journal of Clinical Pharmacy, 1994
- Decomposition Pathways of the Mono- and Bis(Pivaloyloxymethyl) Esters of Azidothymidine 5′-Monophosphate in Cell Extract and in Tissue Culture Medium: An Application of the ‘on-line ISRP-Cleaning’ HPLC TechniqueAntiviral Chemistry and Chemotherapy, 1994
- 9-(2-Phosphonylmethoxyethyl)adenine in the treatment of murine acquired immunodeficiency disease and opportunistic herpes simplex virus infectionsAntimicrobial Agents and Chemotherapy, 1989
- Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent.Proceedings of the National Academy of Sciences, 1989