Inactivation of <i>S-</i>Adenosyl-<scp>l</scp>-homocysteine Hydrolase by Amide and Ester Derivatives of Adenosine-5‘-carboxylic Acid

Wnuk, Stanislaw F.; Liu, Siming; Yuan, Chong‐Sheng; Borchardt, Ronald T.; Robins, Morris J.

doi:10.1021/jm960313y

Cited by 13 publications

(10 citation statements)

References 29 publications

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“…The 6‘( E )-(halohomovinyl)adenosine derivatives D were shown to inactivate AdoHcy hydrolase by catalyzed addition of water to the 5‘,6‘-double bond and generation of the labile homoadenosine-6‘-carboxaldehyde (loss of a proton and halide from C6‘) the 4‘-ethynyl (acetylenic) analogue, and amide or ester derivatives of adenosine- 5‘-carboxylic acid − but no evidence for enzyme-mediated hydrolysis of the amide or ester compounds was observed .…”

Section: Introductionmentioning

confidence: 99%

Anticancer and Antiviral Effects and Inactivation of S-Adenosyl-l-homocysteine Hydrolase with 5‘-Carboxaldehydes and Oximes Synthesized from Adenosine and Sugar-Modified Analogues

et al. 1997

J. Med. Chem.

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Selectively protected adenine nucleosides were converted into 5'-carboxaldehyde analogues by Moffatt oxidation (dimethyl sulfoxide/dicyclohexylcarbodiimide/dichloroacetic acid) or with the Dess-Martin periodinane reagent. Hydrolysis of a 5'-fluoro-5'-S-methyl-5'-thio (alpha-fluoro thioether) arabinosyl derivative also gave the 5'-carboxaldehyde. Treatment of 5'-carboxaldehydes with hydroxylamine [or O-(methyl, ethyl, and benzyl)hydroxylamine] hydrochloride gave E/Z oximes. Treatment of purified oximes with aqueous trifluoroacetic acid and acetone effected trans-oximation to provide clean samples of 5'-carboxaldehydes. Adenosine (Ado)-5'-carboxaldehyde and its 4'-epimer are potent inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. They bind efficiently to the enzyme and undergo oxidation at C3' to give 3'-keto analogues with concomitant reduction of the NAD+ cofactor to give an inactive, tightly bound NADH-enzyme complex (type I cofactor-depletion inhibition). Potent type I inhibition was observed with 5'-carboxaldehydes that contain a ribo cis-2',3'-glycol. Their oxime derivatives are "proinhibitors" that undergo enzyme-catalyzed hydrolysis to release the inhibitors at the active site. The 2'-deoxy and 2'-epimeric (arabinosyl) analogues were much weaker inhibitors, and the 3'-deoxy compounds bind very weakly. Ado-5'-carboxaldehyde oxime had potent cytotoxicity in tumor cell lines and was toxic to normal human cells. Analogues had weaker cytotoxic and antiviral potencies, and the 3'-deoxy compounds were essentially devoid of cytotoxic and antiviral activity.

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Section: Introductionmentioning

confidence: 99%

Anticancer and Antiviral Effects and Inactivation of S-Adenosyl-l-homocysteine Hydrolase with 5‘-Carboxaldehydes and Oximes Synthesized from Adenosine and Sugar-Modified Analogues

et al. 1997

J. Med. Chem.

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“…Oxidation of the 5‘-hydroxymethylene of nucleosides to 5‘-carboxylates is an essential step in the preparation of a number of biologically active molecules . There are relatively few methods describing the general preparation of such nucleoside-5‘-carboxylic acids.…”

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confidence: 99%

Facile Preparation of Nucleoside-5‘-carboxylic Acids

1998

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Oxidation of the 5′-hydroxymethylene of nucleosides to 5′-carboxylates is an essential step in the preparation of a number of biologically active molecules. 1 There are relatively few methods describing the general preparation of such nucleoside-5′-carboxylic acids. Herein, we report a mild procedure for the oxidation of 2′,3′-isopropylideneprotected purine-and pyrimidine-containing nucleosides to their respective 5′-carboxylic acids. This method gives high yields and has a very simple isolation procedure.One of the most widely applied methods for affecting the oxidation of the 5′-hydroxyl of unprotected nucleosides employs molecular oxygen and a platinum catalyst. 2 However, this method affords relatively low yields when applied to 2′,3′-isopropylidene-protected nucleosides. 3 Instead, these nucleosides are most often oxidized using potassium permanganate under strongly alkaline reaction conditions. 4 This limits the potassium permanganate methodology to purine-containing nucleosides. Two other systems used to affect these conversions are CrO 3 /acetic acid 5 and a two-step method involving the generation of the aldehyde followed by oxidation with m-CPBA. 6 However, these methods have not been generally applied.Recently, a method utilizing ruthenium trichloride and sodium periodate under Sharpless conditions was used to obtain the 5′-carboxylic acids of 2′,3′-isopropylidenepurine-containing nucleosides in high yield. 7 Unfortunately, the methodology cannot be used with pyrimidinecontaining nucleosides, as the reaction conditions cause loss of the nucleoside base. Extension of ruthenium trichloride-mediated oxidation to 2′,3′-isopropylidenepyrimidine-containing nucleosides requires the use of both alkaline conditions and potassium persulfate. 8 Thus, many available methods for the generation of nucleoside-5′-carboxylic acids require relatively basic conditions that limit their utility.A recent publication described the oxidation of alcohols to ketones and aldehydes using catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) and stoichiometric amounts of an organic oxidant, [bis(acetoxy)-iodo]benzene (BAIB). 9 The method drew our attention because of its mildness and efficiency. The active oxidant is an N-oxoammonium salt generated by dismutation of TEMPO; BAIB is necessary to regenerate TEMPO by oxidizing the corresponding hydroxylamine of TEMPO. The reaction generates acetic acid and iodobenzene as byproducts and is different from most other TEMPOmediated oxidations in that it avoids inorganic salt contaminants. 9 In addition, N-oxoammonium salt-mediated oxidations are compatible with double and triple bonds, esters, ethers, acetals, epoxides, amides, halides, and azides. Finally, protecting groups such as TBDMS, THP, MOM, Boc, Cbz, benzyl, and acetyl are also stable to the reaction conditions. 10 In the presence of high concentrations of water, Noxoammonium salts convert aliphatic alcohols to their respective carboxylic acids. 10 Since the TEMPO-BAIB system seemed to be a particularly convenient m...

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“…11 In contrast with these results, 10 and the enzymatic hydrolysis of oximes, 9 amide and ester derivatives of adenosine-5′-carboxylic acid underwent oxidation at C3′ by AdoHcy hydrolase (type I, NAD + cofactor-depletion inhibitors 2b ) without observed hydrolysis to the carboxylic acid. 12 We now report analogues of ZDDFA and EDDH-HAs that do not contain the 3′-hydroxyl group (which is oxidized to give 3′-keto intermediates) and their interaction with AdoHcy hydrolase. The 3′-deoxy analogues have major differences in stereoelectronic effects and lack a hydrogen-bond acceptor at C3′.…”

Section: Introductionmentioning

confidence: 94%

“…We had demonstrated that the ( E )-5‘,6‘-didehydro-6‘-deoxy-6‘-halohomoadenosines10a E (EDDHHAs), and especially the homovinyl fluoride 10b F (EDDFHA), could undergo addition of water at C5‘ and C6‘ by AdoHcy hydrolase (hydrolytic activity) without prior oxidation at C3‘ . In contrast with these results, and the enzymatic hydrolysis of oximes, amide and ester derivatives of adenosine-5‘-carboxylic acid underwent oxidation at C3‘ by AdoHcy hydrolase (type I, NAD + cofactor-depletion inhibitors 2b ) without observed hydrolysis to the carboxylic acid . We now report analogues of ZDDFA and EDDHHAs that do not contain the 3‘-hydroxyl group (which is oxidized to give 3‘-keto intermediates) and their interaction with AdoHcy hydrolase.…”

Section: Introductionmentioning

confidence: 99%

Nucleic Acid Related Compounds. 101.S-Adenosyl-l-homocysteine Hydrolase Does Not Hydrate (5‘-Fluoro)vinyl or (6‘-Halo)homovinyl Analogues Derived from 3‘-Deoxyadenosine or 3‘-(Chloro or Fluoro)-3‘-deoxyadenosine¹

Robins

Neschadimenko

et al. 1998

J. Org. Chem.

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The usual mechanistic sequence involves oxidation of AdoHcy at C3′ followed by elimination of L-homocysteine, Michael addition of water, and reduction to give adenosine. A 6′-fluorohomovinyladenosine analogue (EDDFHA) undergoes hydration of the 5′,6′ double bond (hydrolytic activity) at a more rapid rate than oxidation at C3′. Three 4′,5′-didehydro-5′-deoxy-5′-fluoro nucleoside analogues were prepared from 3′-deoxy-and 3′-(chloro and fluoro)-3′-deoxyadenosine via generation of the vinyl fluorides by thermolysis of 5′-fluoro-5′-thioether sulfoxides. The 3′-deoxy analogues of 6′-halohomovinyladenosines were prepared by Wittig extension with a 3′-deoxy-5′-carboxaldehyde and halodestannylation of vinyl stannanes. The 3′-hydroxyl group appears to be essential for binding to AdoHcy hydrolase. No hydrolytic activity at C5′ or C6′ was observed with the nonoxidizable 3′-deoxy or 3′-(chloro or fluoro) analogues in contrast with their 3′-hydroxy counterparts (ZDDFA and EDDFHA). These 3′-modified analogues cannot reduce enzyme-bound NAD + to NADH and do not produce time-dependent inhibition of AdoHcy hydrolase, but are weak competitive inhibitors (K i ) 150-200 µM).

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Inactivation of S-Adenosyl-l-homocysteine Hydrolase by Amide and Ester Derivatives of Adenosine-5‘-carboxylic Acid

Cited by 13 publications

References 29 publications

Anticancer and Antiviral Effects and Inactivation of S-Adenosyl-l-homocysteine Hydrolase with 5‘-Carboxaldehydes and Oximes Synthesized from Adenosine and Sugar-Modified Analogues

Anticancer and Antiviral Effects and Inactivation of S-Adenosyl-l-homocysteine Hydrolase with 5‘-Carboxaldehydes and Oximes Synthesized from Adenosine and Sugar-Modified Analogues

Facile Preparation of Nucleoside-5‘-carboxylic Acids

Nucleic Acid Related Compounds. 101.S-Adenosyl-l-homocysteine Hydrolase Does Not Hydrate (5‘-Fluoro)vinyl or (6‘-Halo)homovinyl Analogues Derived from 3‘-Deoxyadenosine or 3‘-(Chloro or Fluoro)-3‘-deoxyadenosine¹

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Inactivation of S-Adenosyl-l-homocysteine Hydrolase by Amide and Ester Derivatives of Adenosine-5‘-carboxylic Acid

Cited by 13 publications

References 29 publications

Anticancer and Antiviral Effects and Inactivation of S-Adenosyl-l-homocysteine Hydrolase with 5‘-Carboxaldehydes and Oximes Synthesized from Adenosine and Sugar-Modified Analogues

Anticancer and Antiviral Effects and Inactivation of S-Adenosyl-l-homocysteine Hydrolase with 5‘-Carboxaldehydes and Oximes Synthesized from Adenosine and Sugar-Modified Analogues

Facile Preparation of Nucleoside-5‘-carboxylic Acids

Nucleic Acid Related Compounds. 101.S-Adenosyl-l-homocysteine Hydrolase Does Not Hydrate (5‘-Fluoro)vinyl or (6‘-Halo)homovinyl Analogues Derived from 3‘-Deoxyadenosine or 3‘-(Chloro or Fluoro)-3‘-deoxyadenosine1

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Nucleic Acid Related Compounds. 101.S-Adenosyl-l-homocysteine Hydrolase Does Not Hydrate (5‘-Fluoro)vinyl or (6‘-Halo)homovinyl Analogues Derived from 3‘-Deoxyadenosine or 3‘-(Chloro or Fluoro)-3‘-deoxyadenosine¹