3'-Substituted 2',3'-dideoxynucleoside analogs as potential anti-HIV (HTLV-III/LAV) agents

Herdewijn, Piet; Balzarini, Jan; Clercq, Erik De; Pauwels, Rudi; M, Baba; Broder, Samuel; Vanderhaeghe, Hubert

doi:10.1021/jm00391a003

Cited by 301 publications

(83 citation statements)

References 4 publications

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“…Recently, several fluorinated nucleoside analogs have been reported as inhibitors of HIV-1 (10,11,13,14,19,25). However, modification with fluorine was not always advantageous but depended on the position of the fluorine and the combination of fluorination with other modifications of the pentose ring.…”

Section: Resultsmentioning

confidence: 99%

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Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Koshida

Cox

Harmenberg

et al. 1989

Antimicrob Agents Chemother

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One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.

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Section: Resultsmentioning

confidence: 99%

“…Fluorination of 3'-deoxythymidine to give FLT has been shown to result in increased antiviral activity (4,11,13). We tested several other fluorine-substituted thymidine analogs, but none showed greater antiviral activity than FLT.…”

Section: Resultsmentioning

confidence: 99%

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Koshida

Cox

Harmenberg

et al. 1989

Antimicrob Agents Chemother

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“…The first 3' -modification to be investigated was the methanesulphonyl (mesyl) group. It has been shown (Herdewijn, 1987) that 3'-mesyl nucleosides have little or no anti-HIV activity, but it was thus of interest to see if this activity could be improved on by 5' -phosphorylation, and the consequential kinase bypass. Thus, compounds 3a-3c were each mesylated selectively at the 3'-position by treating with mesyl chloride in dichloromethane in the presence of triethylamine (Crossland, 1970).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

McGuigan

Nicholls

O’Connor

et al. 1990

Antivir Chem Chemother

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SummaryThe reaction of thymidine with diethyl, dipropyl, and dibutyl phosphorochloridates yields novel 5/-(dialkyl phosphates), characterized by spectroscopic and analytical data. These are readily mesylated at the 3'-position. Similar reaction of 3'-0-acetyl and 3'-0-ethyl thymidine with dialkyl phosphorochloridates gives an analogous series of compounds. Lastly, reaction of the anti-AIDS drug AZT with these phosphorylating agents gives the corresponding 3'-azido products. It was hoped that these might act as membrane-soluble pro-drugs of the bio-active free nucleotides of AZT and that the alternative 3/ -substituents might also confer similar activity. In fact, none of the compounds studied displayed any anti-HIV activity in vitro. This is attributed to the metabolic stability of the trialkyl phosphate moiety.

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“…The other analogues, which are all inactive (Herdewijn et al, 1987), have neutral or negative C3'-X3' bond polarities.…”

Section: Charge Difference Between C3' and X3'mentioning

confidence: 99%

Conformational Analysis of Substituent Effects on the Sugar Puckering Mode and the anti-HIV Activity of 2′,3′-Dideoxypyrimidine Nucleosides

Everaert

Peeters

Ranter³

et al. 1993

Antivir Chem Chemother

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A comparison between the cdi1formation al parameters of eleven active and inactive anti-HIV· 2',3'-dideoxyp yrimidine nucleosides and a series of 73 uridine and thymidine structures, revealed that our compounds, all having N-glycosidic bond torsion angles X in the anti range, have pseudorotatio n phase angles Pwell distributed over both N (C3 '-endo) and S (C2'-endo and C3' -exo) type sugar conformation s and have both +sc and ap C4' -C5' conformations . This means that solid state conformation s characterized by P, X and "y do not provide decisive information for predicting possible anti-HIV activity. We also found that any rationalization of the activity or inactivity of nucleosides in terms of the gauche effect of electronegative substituents on the furanose ring conformation, could not be demonstrated by using the semiempirica l quantum chemical AM1 method. Calculations of C3'-X3' bond polarities indicate that anti-HIV activity in C3'-substitute d nucleoside analogues is consistent with the presence of a positive C3'-X3' bond polarity. Exploration of the conformationa l space of X vs. "y for C3'-endo, C2'-endo and C3'-exo sugar puckering modes using the same AM1 method, reveals that although the C3'-endo (P = 10°) region is about 2 kcal rnol" lower than the C2'-endo region (P = 170°),the C2'-endo sugar puckering mode is the most accessible one due to the conformationa l flexibility about the minima. Our results also suggest that as P increases from 10°, through 170°,to 210°, the preferred range for v dramatically shifts from almost exclusively

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3'-Substituted 2',3'-dideoxynucleoside analogs as potential anti-HIV (HTLV-III/LAV) agents

Cited by 301 publications

References 4 publications

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

Conformational Analysis of Substituent Effects on the Sugar Puckering Mode and the anti-HIV Activity of 2′,3′-Dideoxypyrimidine Nucleosides

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