Phosphate derivatives of d4T as inhibitors of HIV

McGuigan, Christopher; Sheeka, Hendrika M.; Mahmood, Naheed; Hay, Alan J.

doi:10.1016/s0960-894x(00)80315-7

Cited by 32 publications

(20 citation statements)

References 17 publications

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“…The structures are depicted in Fig. 1 After standing in ice-water for 10 concentration), whereas the formation of d4T-TP and metabolite X started to level off at initial extracellular So324 concentrations higher than 25 ,uM; d4T-TP formation leveled off markedly faster than metabolite X formation. As a result, the ratio of the X levels versus d4T-TP levels progressively increased in function of the initial concentration of the So324 prodrug, and reached more than 200-fold at the highest So324 concentration tested (i.e., 500 ,M) ( Table 2).…”

Section: Methodsmentioning

confidence: 99%

“…The phosphoramidate derivatives of azidothymidine and fluorothymidine (FLT), two good substrates for cytosol TK, have been found to exhibit marked antiviral activity in cell culture (7,8). We have recently focused on masked nucleoside phosphoramidate derivatives of nucleoside analogues [i.e., d4T and dideoxyuridine (ddU)] that have relatively poor affinity for cytosol TK (2,(9)(10)(11). In this study, we revealed that the phosphoramidate derivative of d4T, designated So324, not only proved able to deliver intracellularly the free 5'-monophosphate of d4T (d4T-MP) [leading to pronounced levels of the corresponding active d4T 5'-triphosphate (d4T-TP)], but also released a phosphoramidate derivative of d4T-MP.…”

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confidence: 99%

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Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.

Balzarini

Karlsson

Aquaro

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

114

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So324 is a 2',3'-dideoxy-2',3'-didehydrothymidine-5'-monophosphate (d4T-MP) prodrug containing at the phosphate moiety a phenyl group and the methylester ofalanine linked to the phosphate through a phosphoramidate linkage. So324 has anti-HIV activity in human CEM, MT4, and monocyte/macrophage cells that is superior to that of d4T. In contrast to d4T, So324 is also able to inhibit HIV replication in thymidine kinase-deficient CEM cells. After uptake of So324 by intact human lymphocytes, d4T-MP is released and subsequently converted intracellularly to d4T-TP. In addition, accumulation of substantial amounts of a novel d4T derivative has been found. This d4T metabolite has been characterized as alaninyl d4T-MP. The latter metabolite accumulates at "13-to 200-fold higher levels than d4T-TP depending the experimental conditions. Alaninyl d4T-MP should be considered as an intra-and/or extracellular depot form of d4T and/or d4T-MP. These findings may explain the superior anti-retroviral activity of So324 over d4T in cell culture.2',3'-Dideoxynucleoside (ddN) analogues are potent inhibitors of HIV replication in cell culture. To date, five ddN analogues have been formally licensed for treatment of HIVinfected individuals [(i) zidovudine (azidothymidine; AZT), (ii) zalcitabine (dideoxycytidine; ddC), (iii) didanosine (dideoxyinosine; ddI), (iv) stavudine (didehydrodideoxythymidine; d4T), and (v) lamivudine (3'-thia-2',3'-dideoxycytidine; 3TC)]. The ddN analogues have to be converted to their corresponding 5'-triphosphate derivatives to act as inhibitors of the retroviral reverse transcriptase. However, the rate and extent of phosphorylation of the ddN analogues to their active 5'-triphosphate metabolite may be insufficient. In particular, the first activation (phosphorylation) step may be rate-limiting in that most ddN analogues show poor affinity for nucleoside kinases [i.e., thymidine kinase (TK), 2'-deoxycytidine kinase, adenosine kinase] or other cellular enzymes (i.e., 5'-nucleotidase) that play a crucial role in the conversion of the ddN analogues to their 5'-monophosphates (1-6). In efforts to circumvent the dependence of ddN analogues on activation by the nucleoside kinases, prodrugs of the 5'-monophosphate forms of several nucleoside analogues have been prepared. The phosphoramidate derivatives of azidothymidine and fluorothymidine (FLT), two good substrates for cytosol TK, have been found to exhibit marked antiviral activity in cell culture (7,8). We have recently focused on masked nucleoside phosphoramidate derivatives of nucleoside analogues [i.e., d4T and dideoxyuridine (ddU)] that have relatively poor affinity for cytosol TK (2,(9)(10)(11). In this study, we revealed that the phosphoramidate derivative of d4T, designated So324, not only proved able to deliver intracellularly the free 5'-monophosphate of d4T (d4T-MP) [leading to pronounced levels of the corresponding active d4T 5'-triphosphate (d4T-TP)], but also released a phosphoramidate derivative of d4T-MP. This latter metabolite markedly accumul...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.

Balzarini

Karlsson

Aquaro

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

114

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“…1H, m, H4′), 3.73 (1H, m, H5′), 3.41 (1H, m, CH5′), 1.00 (9H, s, 3 CH 3 -tert-butyl), 0.81 (9H, s, 3 CH 3 -tert-butyl), 0.21 (3H, s, CH 3 -silyl), 0.16 (3H, s, CH 3 -silyl), -0.10 (3H, s, CH 3 -silyl), -0.27 (3H, s, CH 3 -silyl). (12). tBuOK (0.627 g, 4.95 mmol) was added to a solution of 2′,3′-di-O-tert-butyldimethylsilyl-5′-deoxy-5′-iodoadenosine (11, 1.0 g, 1.65 mmol) in pyridine (15 mL), and the reaction was stirred for 3 h at room temperature.…”

Section: Synthesis Of Nn-dibenzoyl-2′3′-di-o-benzoyl-4′-azido-5′-dementioning

confidence: 99%

First Example of Phosphoramidate Approach Applied to a 4‘-Substituted Purine Nucleoside (4‘-Azidoadenosine): Conversion of an Inactive Nucleoside to a Submicromolar Compound versus Hepatitis C Virus

et al. 2007

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We report on the synthesis of the anti hepatitis C virus (HCV) agent 4'-azidoadenosine (1) and the application of the phosphoramidate ProTide technology to this nucleoside. The synthesis of 1 was achieved through an epoxide intermediate followed by regio- and stereoselective ring opening by azidotrimethylsilane in the presence of a Lewis acid. Compound 1 did not inhibit HCV replication in cell culture at concentrations up to 0.1 mM. However, a submicromolar active agent could be derived from 1 by the application of the ProTide technology. All the phosphoramidates prepared were L-alanine derivatives with variations in the aryl moiety and in the ester part of the amino acid. The benzyl ester and the l-naphthyl phosphate (18) had the best activity in replicon assay. Phosphoramidates (18-21) achieved a significant improvement in antiviral potency over the parent nucleoside (1) with no increase in cytotoxicity.

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“…32 With the exception of 3 H -acetyl, 3 H -ethyl, and 3 H -mesyl thymidine, bis(2,2,2-trihaloalkyl), simple alkyl, and mixed alkyl haloalkyl phosphates of thymidine analog antiviral nucleosides (i.e., d4T, and AZT) were found to be less potent against HIV-1 in C8166 cells than the parent nucleosides. 27,30,31,35,36 Glycolate and lactate analogs of d4T were also examined, but were not found to be particularly active against HIV-1 or HIV-2 in the human T-lymphocyte CEM/0 and CEM/TK À cell lines ( Fig. 3).…”

Section: Alkyl and Aryl Phosphotriestersmentioning

confidence: 99%

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Wagner¹,

Iyer²,

McIntee³

2000

Med. Res. Rev.

264

215

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To overcome the many hurdles preventing the use of antiviral and anticancer nucleosides as therapeutics, the development of a prodrug methodology (i.e., pronucleotide) for the in vivo delivery of nucleotides has been proposed as a solution. The ideal pronucleotide should be non‐toxic, stable in plasma and blood, capable of being i.v. and/or orally dosed, and intracellularly convertible to the corresponding nucleotide. Although this goal has yet to be achieved, many clever and imaginative pronucleotide approaches have been developed, which are likely to be important pharmacological tools. This review will discuss the major advances and future directions of the emerging field of antiviral and anticancer pronucleotide design and development. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 6, 417–451, 2000

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Phosphate derivatives of d4T as inhibitors of HIV

Cited by 32 publications

References 17 publications

Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.

Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.

First Example of Phosphoramidate Approach Applied to a 4‘-Substituted Purine Nucleoside (4‘-Azidoadenosine): Conversion of an Inactive Nucleoside to a Submicromolar Compound versus Hepatitis C Virus

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

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