Analogues of S-adenosylhomocysteine as potential inhibitors of biological transmethylation. Synthesis of analogues with modifications at the 5'-thioether linkage

Chang, Chi‐Deu; Coward, James K.

doi:10.1021/jm00227a021

Cited by 41 publications

(7 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… Synthesis of 2‐( S , R )‐benzyloxycarbonylamino‐4‐iodobutyrate ( 6a , b ) [43,45]. i/: a, Na 2 CO 3 aq., benzyl chloroformate, 0 °C, 4 h; b, benzyl bromide/dimethylformamide, 0 °C, 2 days; (35%).…”

Section: Methodsmentioning

confidence: 99%

“…Commercially available ( R , S )‐homoserine was transformed into ( R , S )‐2‐benzyloxycarbonylamino‐4‐iodobutyrate ( 6a , b ) [43,45] (Scheme 2), and this was used for addition of the amino acid to the nucleobase N‐3 position (Scheme 1).…”

Section: Methodsmentioning

confidence: 99%

“…The homogeneity and structure of the desired nucleosides were confirmed by spectral analysis data (NMR and MS), and compared with the respective data of the products obtained in the alternative way, via hydrogenolysis of 1c,d into 2c,d under more drastic conditions [10% Pd ⁄ C, H 2 1 atm., EtOH ⁄ H 2 O 1 : 1 (v ⁄ v), 1.5 equivalent acetic acid, 5 days] (Scheme 1, i¢). [43,45]. i ⁄ : a, Na 2 CO 3 aq., benzyl chloroformate, 0°C, 4 h; b, benzyl bromide ⁄ dimethylformamide, 0°C, 2 days; (35%).…”

Section: Synthesis Of Acp 3 Dmentioning

confidence: 99%

See 2 more Smart Citations

3‐(3‐amino‐3‐carboxypropyl)‐5,6‐Dihydrouridine is one of two novel post‐transcriptional modifications in tRNA^Lys(UUU) from Trypanosoma brucei

et al. 2011

View full text Add to dashboard Cite

tRNA is the most heavily modified of all RNA types, with typically 10-20% of the residues being post-transcriptionally altered. Unravelling the modification pattern of a tRNA is a challenging task; there are 92 currently known tRNA modifications [1], many of which are chemically similar. Furthermore, the tRNA has to be investigated with single-nucleotide resolution in order to ensure complete mapping of all modifications. In the present work, we characterized tRNA Lys (UUU) from Trypanosoma brucei, and provide a complete overview of its post-transcriptional modifications. The first step was MALDI-TOF MS of two independent digests of the tRNA, with RNase A and RNase T1, respectively. This revealed digestion products harbouring mass-changing modifications. Next, the modifications were mapped at the nucleotide level in the RNase products by tandem MS. Comparison with the sequence of the unmodified tRNA revealed the modified residues. The modifications were further characterized at the nucleoside level by chromatographic retention time and fragmentation pattern upon higherorder tandem MS. Phylogenetic comparison with modifications in tRNA Lys from other organisms was used through the entire analysis. We identified modifications on 12 nucleosides in tRNA Lys (UUU), where U47 exhibited a novel modification, 3-(3-amino-3-carboxypropyl)-5,6-dihydrouridine, based on identical chromatographic retention and MS fragmentation as the synthetic nucleoside. A37 was observed in two versions: a minor fraction with the previously described 2-methylthio-N 6 -threonylcarbamoyl-modification, and a major fraction with A37 being modified by a 294.0-Da moiety. The latter product is the largest adenosine modification reported so far, and we discuss its nature and origin.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Synthesis Of Acp 3 Dmentioning

confidence: 99%

See 1 more Smart Citation

3‐(3‐amino‐3‐carboxypropyl)‐5,6‐Dihydrouridine is one of two novel post‐transcriptional modifications in tRNA^Lys(UUU) from Trypanosoma brucei

et al. 2011

View full text Add to dashboard Cite

show abstract

“…They not only serve as potential therapeutics but also are useful chemical probes for MTase biology study. SAM/SAH analogs have long been recognized and studied as small molecule inhibitors, with much work on structural modifications on the amino acid chain, sugar, and base portions by Borchardt, Wu, and others. − Below, we discuss the recent development of SAM/SAH-based MTase inhibitors.…”

Section: Development Of Sah Analogs As Mtase Inhibitorsmentioning

confidence: 99%

SAM/SAH Analogs as Versatile Tools for SAM-Dependent Methyltransferases

2015

View full text Add to dashboard Cite

S -Adenosyl-L-methionine (SAM) is a sulfonium molecule with a structural hybrid of methionine and adenosine. As the second largest cofactor in the human body, its major function is to serve as methyl donor for SAM-dependent methyltransferases (MTases). The resultant transmethylation of biomolecules constitutes a significant biochemical mechanism in epigenetic regulation, cellular signaling, and metabolite degradation. Recently, numerous SAM analogs have been developed as synthetic cofactors to transfer the activated groups on MTase substrates for downstream ligation and identification. Meanwhile, new compounds built upon or derived from the SAM scaffold have been designed and tested as selective inhibitors for important MTase targets. Here, we summarized the recent development and application of SAM analogs as chemical biology tools for MTases.

show abstract

“…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.…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

Analogues of S-adenosylhomocysteine as potential inhibitors of biological transmethylation. Synthesis of analogues with modifications at the 5'-thioether linkage

Cited by 41 publications

References 18 publications

3‐(3‐amino‐3‐carboxypropyl)‐5,6‐Dihydrouridine is one of two novel post‐transcriptional modifications in tRNA^Lys(UUU) from Trypanosoma brucei

3‐(3‐amino‐3‐carboxypropyl)‐5,6‐Dihydrouridine is one of two novel post‐transcriptional modifications in tRNA^Lys(UUU) from Trypanosoma brucei

SAM/SAH Analogs as Versatile Tools for SAM-Dependent Methyltransferases

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

Contact Info

Product

Resources

About

Analogues of S-adenosylhomocysteine as potential inhibitors of biological transmethylation. Synthesis of analogues with modifications at the 5'-thioether linkage

Cited by 41 publications

References 18 publications

3‐(3‐amino‐3‐carboxypropyl)‐5,6‐Dihydrouridine is one of two novel post‐transcriptional modifications in tRNALys(UUU) from Trypanosoma brucei

3‐(3‐amino‐3‐carboxypropyl)‐5,6‐Dihydrouridine is one of two novel post‐transcriptional modifications in tRNALys(UUU) from Trypanosoma brucei

SAM/SAH Analogs as Versatile Tools for SAM-Dependent Methyltransferases

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

Contact Info

Product

Resources

About

3‐(3‐amino‐3‐carboxypropyl)‐5,6‐Dihydrouridine is one of two novel post‐transcriptional modifications in tRNA^Lys(UUU) from Trypanosoma brucei

3‐(3‐amino‐3‐carboxypropyl)‐5,6‐Dihydrouridine is one of two novel post‐transcriptional modifications in tRNA^Lys(UUU) from Trypanosoma brucei