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 virus

Balzarini, Jan; Kruining, J.; Wedgwood, Orson; Pannecouque, Christophe; Aquaro, Stefano; Perno, Carlo Federico; Naesens, Lieve; Witvrouw, Myriam; Heijtink, R. A.; Clercq, Erik De; McGuigan, Christopher

doi:10.1016/s0014-5793(97)00616-9

Cited by 62 publications

(51 citation statements)

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“…Such success was also observed with 2',3'-didehydro-2',3'-dideoxyadenosine (d4 A, 21), [51] 2',3'-dideoxyadenosine (ddA, 22) [51] and 2',3'-dideoxy-3'-fluoroadenosine (3'-F-ddA, 23) [52] .…”

Section: '-Azidouridinementioning

confidence: 75%

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

2009

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Prodrug technologies aimed at delivering nucleoside monophosphates into cells (protides) have proved to be effective in improving the therapeutic potential of antiviral and anticancer nucleosides. In these cases, the nucleoside monophosphates are delivered into the cell, where they may then be further converted (phosphorylated) to their active species. Herein, we describe one of these technologies developed in our laboratories, known as the phosphoramidate protide method. In this approach, the charges of the phosphate group are fully masked to provide efficient passive cell-membrane penetration. Upon entering the cell, the masking groups are enzymatically cleaved to release the phosphorylated biomolecule. The application of this technology to various therapeutic nucleosides has resulted in improved antiviral and anticancer activities, and in some cases it has transformed inactive nucleosides to active ones. Additionally, the phosphoramidate technology has also been applied to numerous antiviral nucleoside phosphonates, and has resulted in at least three phosphoramidate-based nucleotides progressing to clinical investigations. Furthermore, the phosphoramidate technology has been recently applied to sugars (mainly glucosamine) in order to improve their therapeutic potential. The development of the phosphoramidate technology, mechanism of action and the application of the technology to various monophosphorylated nucleosides and sugars will be reviewed.

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Section: '-Azidouridinementioning

confidence: 75%

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

2009

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“…Always EC 50 values as well as CC 50 values >250 µM were found. Apparently, the diols are neither responsible for the antiviral activity nor cause toxicity.…”

Section: Cyclosal-nucleotidesmentioning

confidence: 93%

Section: Nucleoside Arylphosphoramidatesmentioning

confidence: 99%

“…In contrast to the previously mentioned phosphotriester approaches, in this case the structural motive involves a phosphate moiety that is linked to the nucleoside, a phenyl group and, through a phosphoramidate linkage, also to the methyl ester of α-amino acid ester. This concept has been applied to the wide variety of nucleotides active against several viruses: d4TMP (47) , AZTMP (48) , 3'-thiacytidine monophosphate (3TCMP) (49) , ddAMP (50) and 2',3'-dideoxy-2',3'-didehydroadenosine monophosphate (d4AMP) (50,51) .In in vitro antiviral tests, the d4T containing phosphoramidate was found to be slightly active as the parent nucleoside in wild-type CEM/O and MT-4 cells. More importantly and in contrast to d4T 1, the d4TMP phosphoramidate completely retained the biological activity in mutant thymidine kinase-deficient CEM/TK -cells (47) and suppresses HIV-1 infection in natural peripheral blood lymphocytes and freshly isolated monocyte/macrophages.…”

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confidence: 99%

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Pro-Nucleotides - Recent Advances in the Design of Efficient Tools for the Delivery of Biologically Active Nucleoside Monophosphates

Meier¹

1998

Synlett

113

102

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A summary of the most recent advances to the design of pronucleotides will be presented. Approaches that have been designed to be activated by enzymes such as carboxyesterases [bis(POM)-, bis(POC)-, bis(SATE)-, bis(AB) phosphotriesters and the arylphosphoramidates] or by reductases [bis(SDTE) approach] will be discussed as well as the amino acids phosphoramidate diester concept with its still unknown delivery mechanism and the cycloSal approach that releases the nucleotides by an induced tandem reaction.Nucleoside analogues, e.g. 2',3'-dideoxy-2',3'-didehydrothymidine 1 (d4T), 3'-azido-2',3'-dideoxythymidine 2 (AZT) or 5-fluoro-2'-deoxyuridine 3 (5-FdU), are structurally different as compared to the corresponding natural DNA or RNA nucleosides with regard to modification of the glycon as well as the aglycon residue. Due to this modified structure, these compounds are widely used as antiviral or antitumor drugs in chemotherapy ( Figure 1) (1) . Since the discovery of AZT 2 as the first nucleoside drug for the treatment of AIDS, considerable efforts have been made to develop new nucleoside analogues that would be more active, less toxic inhibitors of the HIV-1 reverse transcriptase (RT) (2) . The general mode of action of nucleoside analogues is the inhibition of the HIV-1 RT by acting as competitive inhibitors or as DNA chain terminators. To act as DNA chain termination agents or RT inhibitors, intracellular conversion of the nucleoside analogues into their 5'-mono-, 5'-di-or 5'-triphosphates is a prerequisite after cell penetration (3) . The enormous disparity in anti-HIV activity that is evident for a large number of dideoxynucleoside analogues belies their apparent structural similarity. Due to these structural differences as compared to natural nucleosides the metabolization to the corresponding dideoxynucleoside triphosphates is often inefficient and consequently the therapeutic efficacy is sometimes limited (4) . For example, in the case of the anti-HIV active dideoxynucleoside analogue d4T 1 (Stavudine, Zerit ® ) (5) the first phosphorylation to d4T 5'-monophosphate 4 catalyzed by thymidine kinase (TK) is the rate-limiting step in human cells (6) . More striking, however is 2',3'-dideoxyuridine triphosphate (ddUTP) which is one of the most powerful and selective inhibitors of HIV reverse transcriptase (K i = 0.05 µM) while the parent nucleoside 2',3'-dideoxyuridine 5 (ddU) is virtually ineffective at blocking HIV infection in cultured cells. Biochemical and pharmacological studies in three different human T cell lines (CEM, showed that ddU 5 itself was not anabolized to the 5'-monophosphate, most apparently because it was a poor substrate for cellular nucleoside kinases because of the considerable substrate specificity of these enzymes (7) . In contrast, in a few cases the limited efficacy is also due to a catabolic enzymatic reaction. For example, 2',3'-dideoxyadenosine 6 (ddA) is rapidly intracellularly deaminated to ddI 7 by adenosine deaminase (ADA) (8,9) . As a consequence, ddI 7 has to ...

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“…29 and TI values of 466.9 and 354.5, respectively. Finally, Balzarini et al [41] studied the anti-retrovirus and anti-HBV activity of d4A aryloxyphosphoramidate derivative 17 (Cf 1001) (Fig. 10) in various cell culture models.…”

Section: 3 -Unsaturated Nucleosidesmentioning

confidence: 99%

Σύνθεση Μιας Νέας Τάξης Φθορο - Θειο - Νουκλεοζιτών Με Πιθανή Αντιϊκή Και Αντικαρκινική Δράση

Τσουκαλά¹

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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 virus

Cited by 62 publications

References 20 publications

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

Pro-Nucleotides - Recent Advances in the Design of Efficient Tools for the Delivery of Biologically Active Nucleoside Monophosphates

Σύνθεση Μιας Νέας Τάξης Φθορο - Θειο - Νουκλεοζιτών Με Πιθανή Αντιϊκή Και Αντικαρκινική Δράση

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