Biologic activities of poly (2-azaadenylic acid) and poly (2-azainosinic acid)

Clercq, Erik De; Huang, Guang-Fu; Torrence, Paul F.; Fukui, Toshikazu; Kakiuchi, Nobuko; Ikehara, Morio

doi:10.1093/nar/4.10.3643

Cited by 14 publications

(2 citation statements)

References 17 publications

(26 reference statements)

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“…From an inspection of Figs. 1 and 2 and the corresponding Figures in previous publications (De Clercq et al, 1975bClercq et al, , 1976Clercq et al, , 1977, (fl2A). would also appear far more potent than other (A), analogues for which the K, values have not been determined, i.e.…”

Section: Discussionmentioning

confidence: 70%

Inhibition of murine leukaemia virus reverse transcriptase by 2-halogenated polyadenylic acids

Fukui¹,

Clercq²

1982

Biochemical Journal

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Several new analogues of polyadenylic acid [(A)n], i.e. poly(2-fluoroadenylic acid) [(fl2A)n], poly(2-chloroadenylic acid [(cl2A)n], poly(2-bromoadenylic acid) [(br2A)n] and poly(2-iodoadenylic acid) [(io2A)n] have been synthesized and evaluated for their effects on the RNA-directed DNA polymerase (reverse transcriptase) activity of Moloney murine leukaemia virus. All (A)n analogues were found to be potent inhibitors of reverse transcriptase, the order of (decreasing) potency being (fl2A)n greater than (io2A)n greater than (br2A)n greater than (cl2A)n. For all four (A)n analogues the inhibition of reverse transcriptase was competitive with respect to the template-primer. (A)n . oligo(dT). The K1 values were 0.02 microgram/ml for (fl2A)n, 0.1 microgram/ml for (io2A)n, 0.5 microgram/ml for (br2A)n and 8 microgram/ml for (cl2A)n. With a Ki of 0.02 microgram/ml (approx. 0.04 microM), (fl2A)n can be considered as one of the most, if not the most, potent polynucleotide inhibitor of reverse transcriptase that has been described so far.

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Section: Discussionmentioning

confidence: 70%

Inhibition of murine leukaemia virus reverse transcriptase by 2-halogenated polyadenylic acids

Fukui¹,

Clercq²

1982

Biochemical Journal

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“…This enzyme had been discovered in 1970 by Temin and Mizutani [8] and Baltimore [9] and thus started the search for reverse transcriptase inhibitors, focusing initially on single-stranded polynucleotides as they might inhibit the enzyme by competing with the single-stranded genome of the oncoviruses, then believed to be at the origin of leukaemia and other cancers. Thus, again in collaboration with Ikehara, we described several polynucleotides, that is, poly(2-methylthioinosinic acid) [10], poly(2-azaadenylic acid) [11] and various 2-and 2′-substituted polyadenylic acids [12], as inhibitors of the oncovirus reverse transcriptase. Yet, as the interest and belief in the possible role of the reverse transcriptase in human cancer waned, so did the interest in the pursuit of polynucleotides as reverse transcriptase inhibitors.…”

Section: Polynucleotidesmentioning

confidence: 99%

Antiviral Drug Development – Success and Failure: A Personal Perspective with a Japanese Connection

Clercq

2013

Antivir Chem Chemother

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At the 25th International Conference on Antiviral Research, I received a special recognition for my contribution to the International Society of Antiviral Research over a period of 25 years (from 1987 until 2012). This review follows the theme of my presentation at that event, which comprised 10 reminiscences, all with a Japanese connection concerning the success, or otherwise, in the clinical development of: double- and single-stranded polynucleotides; suramin, a polysulfonate; dextran sulfate, a polysulfate; brivudin; BVaraU; 2′,3′-dideoxynucleoside analogues; HEPT; adefovir and tenofovir; CXCR4 antagonists; and elvitegravir.

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Stereoselective synthesis of 2‐azapurine 2′‐deoxy‐β‐D‐ribonucleosides by nucleobase‐anion glycosylation

Kazimierczuk

Seela

1990

Liebigs Ann. Chem.

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Nucleobase-anion glycosylation of 6-(methylthio)-2-azapurine been assigned on the basis of the 'H-NOE difference spectral (1) with 2-deoxy-3,5-di-O-(p-toluoyl)-a-~-erythro-pentofura-data in combination with gated-decoupled 13C-NMR and senosy1 chloride (2) yields the 2'-deoxy-P-D-ribofuranosides 3 -5 lective INEPT spectroscopy. The regioisomeric 6-methylthio stereoselectively. The distribution of regioisomers is as fol-nucleosides have been converted into 6-substituted derivalows: N-9 (32%); N-2 (30%), and N-7 (7%) together with a minor tives of biological interest including 2'-deoxy-2-azaadenosine amount of an unidentified labile glycosylation product. The (8). Compound 8 is a substrate of adenosine deaminase. anomeric configuration and the site of glycosylation have Replacement of C-2 in purine nucleosides by nitrogensystematic and purine numbering (the latter indicated in parentheses) are used in this paper -leads to imidazo[4,5-d]-1,2,3-triazine (2-azapurine) derivatives exhibiting interesting biological functions '). Up to now the synthesis of 2-azapurine ribo-and 2'-deoxyribo-and arabinonucleosides as well as of CI-D or acyclo analogues is based almost entirely on ring annulation of imidazole nucleosides' -7). Only in one case the glycosylation of a 2-azapurine derivative with a P-D-ribofuranosyl halide has been described').In 1983 we reported on the stereoselective synthesis of pyrrolo[2,3-d]pyrimidine 2'-deoxy-P-~-ribonucleosides employing the nucleobase anion''. Later, other 2'-deoxyribonucleosides have been synthesized stereoselectively'0-12). In the following we report on the glycosylation of the 2-azapurine 1 with 2-deoxy-3,5-di-O-(p-toluoyl)-a-~-erythro-pentofuranosyl chloride (2). Results and Discussion 4-(Methylthio)-7H-imidazo[4,5-d]-1,2,3-triazine (6-(methylthi0)-2-azapurine)'~)(1) has been chosen as starting material because the methylthio group can be displaced by various nucleophiles thus forming compounds of biological interest. Another potential candidate -6-chloro-2-azapuTreatment of compound 3 with sodium methoxide furnishes the deblocked nucleoside 6 indicating that the methylthio group is readily displaced by nucleophiles. The same process occurs with the regioisomer 4 which is deprotected under the same conditions to compound 9. In contrast, therinei4' -has not been employed, due to the high reactivity of the chloro substituent and facile opening of the 6-memThe anion of 1 is generated either with solid potassium hydroxide/tris[2-(2-methoxyethoxy)ethyl]amine (KOH/ TDA-1)i6) or NaH'') in acetonitrile. The reaction of this four glycosylation products in almost identical yields. Three of these (3, 4, and 5) give satisfactory elemental analyses, tempts to elucidate its structure or to prepare derivatives have been unsuccessful.

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Biologic activities of poly (2-azaadenylic acid) and poly (2-azainosinic acid)

Cited by 14 publications

References 17 publications

Inhibition of murine leukaemia virus reverse transcriptase by 2-halogenated polyadenylic acids

Inhibition of murine leukaemia virus reverse transcriptase by 2-halogenated polyadenylic acids

Antiviral Drug Development – Success and Failure: A Personal Perspective with a Japanese Connection

Stereoselective synthesis of 2‐azapurine 2′‐deoxy‐β‐D‐ribonucleosides by nucleobase‐anion glycosylation

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