Chemoenzymic Synthesis of 4-Substituted Riboses. S-(4'-Methyladenosyl)-L-homocysteine

Johnson, Carl R.; Esker, John L.; Zandt, M.C. Van

doi:10.1021/jo00099a005

Cited by 37 publications

(24 citation statements)

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“…P. Serafinowski et al have demonstrated that a suitably protected L-homocystine can be condensed with unprotected nucleosides under Hata's condition to give the protected AdoHcy analogs. 11,12) The direct condensation of 3 with N,N-bis(trifluoroacetyl)-L-homocystine dimethyl ester 11,13) (13) in the presence of tri-n-butylphosphine proved unsuccessful as expected. However, with the amino-protected quinazoline nucleoside (15) prepared from 3, the coupling reaction proceeded but only gave 5% of the desired product 16 accompanied with unreacted starting materials.…”

Section: Resultsmentioning

confidence: 82%

“…3,4) S-Adenosyl-L-homocysteine (1, AdoHcy), the byproduct of these AdoMet-dependent transmethylations, and some of its structural analogs have been shown to be potent competitive product inhibitors of the AdoMet-dependent methyltransferases. [5][6][7][8][9][10][11][12][13][14][15] Our group has also been interested in the synthesis and biological evaluation of several 5Ј-sulfur containing nucleosides. [16][17][18] In continuation of our studies and our longstanding interest in the biological activities of quinazoline derivatives, 19) we initiated an investigation on the synthesis and biological evaluation of 5Ј-sulfur containing quinazoline nucleoside derivatives.…”

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confidence: 99%

“…Acknowledgments We thank professor Carl R. Johnson of Wayne State University (MI, U.S.A.) for his valuable suggestions for the preparation of the protected L-homocystine (13). This investigation was supported by a research grant (NSC84-2331-B-016-018) from the National Science Council of Taiwan.…”

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confidence: 99%

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Nucleosides: XI. Synthesis and Antiviral Evaluation of 5'-Alkylthio-5'-deoxy Quinazolinone Nucleoside Derivatives as S-Adenosyl-L-homocysteine Analogs

Chien

Chen

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Several nucleosides containing 5Ј-sulfur substituents have been discovered in nature and are involved in many important biological processes. One of the most significant processes is the S-adenosyl-L-methionine (AdoMet)-dependent transmethylations. Inhibition of these methyl transfer processes has been correlated with antiviral activity and has attracted considerable attention as a target for the discovery of new antiviral agents.3,4) S-Adenosyl-L-homocysteine (1, AdoHcy), the byproduct of these AdoMet-dependent transmethylations, and some of its structural analogs have been shown to be potent competitive product inhibitors of the AdoMet-dependent methyltransferases.5-15) Our group has also been interested in the synthesis and biological evaluation of several 5Ј-sulfur containing nucleosides. [16][17][18] In continuation of our studies and our longstanding interest in the biological activities of quinazoline derivatives, 19) we initiated an investigation on the synthesis and biological evaluation of 5Ј-sulfur containing quinazoline nucleoside derivatives.Quinazoline nucleosides were first synthesized by Stout and Robins in 1968 as pyrimidine nucleoside analogs 20) and consequent synthetic studies were contributed by Dunkel and Pfleiderer in the 1990s. [21][22][23] Quinazoline nucleosides were once used as a conformationally restricted model to study the syn-anti conformational preference of pyrimidine nucleosides in solution. 24,25) More recently, quinazoline nucleosides have been incorporated into oligonucleotides as pyrimidine nucleoside substitutes to study the binding affinity and basepairing selectivity.26) However, their biological activities are still relatively less known in literature. 4-Amino-1-(b-D-ribofuranosyl)quinazolin-2-one (3) was chosen for our study. This quinazoline nucleoside was previously synthesized from quinazoline-2,4-dione by Stout and Robins as a cytidine (2) analog, 20) and subsequently shown to display the antiviral activity against herpes simplex virus.27) Other derivatives from this nucleoside have rarely been studied. 20,21) In an effort to explore the antivirial profiles and the chemical properties of the 4-aminoquinazolin-2-one nucleoside (3), two target structures containing 5Ј-sulfur substituents (4, 5) were designed as S-adenosyl-L-homocysteine (1, AdoHcy) analogs. Herein, we report an improved synthesis of 3 and the synthesis of 5Ј-alkylthio-5Ј-deoxy quinazolinone nucleosides 4 and 5. Results and DiscussionA perusal of the literature revealed that most of 4-aminoquinazolin-2-one nucleosides were synthesized by ribosylation of quinazoline-2,4-diones followed by functional group interconversions.20,21) Our first effort was to develop a direct synthetic route from 4-aminoquinazolin-2-one 28,29) (7). The heterocycle 7 was prepared via a 1,3-dicyclohexylcarbodiimide (DCC)-mediated cyclodesulfurative annulation reaction developed in our laboratory.30,31) Anthranilamide (6) was condensed with benzoyl isothiocyanate to form the thiourea intermediate which was immediately treated wi...

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Section: Resultsmentioning

confidence: 82%

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Nucleosides: XI. Synthesis and Antiviral Evaluation of 5'-Alkylthio-5'-deoxy Quinazolinone Nucleoside Derivatives as S-Adenosyl-L-homocysteine Analogs

Chien

Chen

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The 4- C -substituted riboses can be prepared either by manipulation of natural carbohydrates[24] or chemoenzymatic strategy from non-sugar precursors. [25, 26] From the method available, we chose Maddaford’s method for diastereoselective incorporation of the alkyl substituent into the 4 position of D-ribose ring by addition of Grignard reagents to 4-ulose. [24] Reduction of the protected ribose 6 with NaBH 4 provided the acyclic ribitol 7 (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

S-Ribosylhomocysteine analogues modified at the ribosyl C-4 position

Chbib

Sobczak

Mudgal

et al. 2016

Journal of Sulfur Chemistry

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4-C-Alkyl/aryl-S-ribosylhomocysteine (SRH) analogues were prepared by coupling of homocysteine with 4-substituted ribofuranose derivatives. The diastereoselective incorporation of the methyl substituent into the 4 position of the ribose ring was accomplished by addition of methylmagnesium bromide to the protected ribitol-4-ulose yielding the 4-C-methylribitol in 85% yield as single 4R diastereomer. The 4-C hexyl, octyl, vinyl, and aryl ribitols were prepared analogously. Chelation controlled addition of a carbanion to ketones from the (Si-face) was responsible for the observed stereochemical outcome. Oxidation of the primary alcohol of the 4-C ribitols with the catalytic amount of tetrapropylammonium perruthenate in the presence of N-methylmorpholine N-oxide produced 4-C-alkylribono-1,4-lactones in high yields. Mesylation of the latter compounds at the 5-hydroxyl position and treatment with a protected homocysteine thiolate afforded protected 4-C-alkyl/aryl-SRH analogues as the lactones. Reduction with lithium triethylborohydride and successive global deprotections with TFA afforded 4-C-alkyl/aryl SRH analogues. These analogues might impede the S-ribosylhomocysteinase(LuxS)-catalyzed reaction by preventing β-elimination of a homocysteine molecule, and thus depleting the production of quorum sensing signaling molecule AI-2.

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“…Employing the alternative strategy, in which a 4'-Cbranch is directly attached to a suitable protected nucleoside and then converted to the desired functional group, only a few methods are known [17,18,19] and most of them are not stereoselective or allow only a limited type of functional groups. The most promising method applying an aldol reaction was initially reported for a ribonucleoside [20], and then also applied to thymidine and other 2'-deoxynucleosides (Scheme 4) [21].…”

Section: Nucleosides With Hydrophobic 4'-c-modificationsmentioning

confidence: 99%

Synthesis of 4-C-modified 2-Deoxyribonucleoside Analogues and Oligonucleotides

Marx¹,

Jung

2008

COC

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4'-C-Modified nucleotides and oligonucleotides have been explored extensively recently. The motivations for these investigations drive from the development of new drugs to investigations of complex biological processes. This review covers the common strategies for the synthesis of 4'-C-modified nucleosides that have been subsequently incorporated into oligonucleotides. After a brief depiction of two mainly followed routes for the generation of 4'-C-modified nucleosides, the synthetic efforts of the modified nucleotides are grouped into those bearing hydrophobic or polar modifications. Subsequently strategies for the incorporation of the respective nucleotides into oligonucleotides by automated DNA synthesis are discussed. O OPG B HO O J K H CH 2 O 2'-deoxynucleoside

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Chemoenzymic Synthesis of 4-Substituted Riboses. S-(4'-Methyladenosyl)-L-homocysteine

Cited by 37 publications

References 0 publications

Nucleosides: XI. Synthesis and Antiviral Evaluation of 5'-Alkylthio-5'-deoxy Quinazolinone Nucleoside Derivatives as S-Adenosyl-L-homocysteine Analogs

Nucleosides: XI. Synthesis and Antiviral Evaluation of 5'-Alkylthio-5'-deoxy Quinazolinone Nucleoside Derivatives as S-Adenosyl-L-homocysteine Analogs

S-Ribosylhomocysteine analogues modified at the ribosyl C-4 position

Synthesis of 4-C-modified 2-Deoxyribonucleoside Analogues and Oligonucleotides

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