Nucleoside peptides. I. Synthesis of 5'-deoxy-5'amino-5'-N-aminoacyl peptide derivatives of guanosine, adenosine, and 2'-deoxyadenosine and their effect of cell-free protein synthesis

Robins, Morris J.; Simon, Lionel N.; Stout, M.G.; Ivánovics, G.; Schweizer, Martin; Rousseau, Robert; Robins, Roland K.

doi:10.1021/ja00735a025

Cited by 14 publications

(8 citation statements)

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“…37 Hence, the 5′-amino group of the nucleoside ribose moiety was chosen as a site of diversification through robust peptidyl chemistry in order to prepare the target library of 5′-amido derivatives 4-34 (Scheme 1). The resulting nucleoside peptide library was expected to show reasonable stability to dissolution, storage and screening as evidenced for similar aminoacyl functions found in various nucleoside antibiotics such as puromycin, gougerotin, amicetin, and blasticidin S, all known inhibitors of protein synthesis.…”

Section: Introductionmentioning

confidence: 99%

Parallel Solution-Phase Synthesis of an Adenosine Antibiotic Analog Library

Moukha-Chafiq

Reynolds

2013

ACS Comb. Sci.

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A library of eighty one adenosine antibiotic analogs was prepared under the Pilot Scale Library Program of the NIH Roadmap initiative from 5′-amino-5′-deoxy-2′,3′-O-isopropylidene-adenosine 3. Diverse aldehyde, sulfonyl chloride and carboxylic acid reactant sets were condensed to 3, in solution-phase fashion, leading after acid-mediated hydrolysis to the targeted compounds in good yields and high purity. No marked anti-tuberculosis or anticancer activity was noted on preliminary cellular testing, but these nucleoside analogs should be useful candidates for other types of biological activity.

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Section: Introductionmentioning

confidence: 99%

Parallel Solution-Phase Synthesis of an Adenosine Antibiotic Analog Library

Moukha-Chafiq

Reynolds

2013

ACS Comb. Sci.

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“…The structural difference between 8a and 13a resides in the sugar moiety; it is certain that the interactions between the dipeptide-conjugated nucleoside and the RNA duplex are related to the sugar-pucker conformation of the nucleoside, which further affects the base stacking and the nonbonding interactions. (6). To a soln.…”

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confidence: 97%

“…Actually, many naturally occurring or synthesized peptide-conjugated nucleosides have shown antibacterial or antiviral activities [5]. In the early years, Robins and co-workers indicated that some natural nucleosideÀpeptides were inhibitors of protein synthesis, and peptides bound to DNA may play a role in protein synthesis by acting as −derepressors× of structural genes [6]. Puromycin, an amino acid conjugated nucleoside, resembles the structure of the 3'-end of aminoacyl-tRNA which can bind to the ribosomal A-site [7].…”

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confidence: 99%

Solid‐Phase Synthesis of Dipeptide‐Conjugated Nucleosides and Their Interaction with RNA

Dong

Zhang

2003

Helvetica Chimica Acta

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Dipeptide-conjugated nucleosides were efficiently synthesized from the intermediates of 3'-amino-3'-deoxy-nucleosides by using the solid-phase synthetic strategy with HOBt/HBTU (1-hydroxy-1H-benzotriazole/ 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoroborate) as the coupling reagents (Schemes 1 ± 3). CD Spectra and thermal melting studies showed that the synthesized hydrophobic dipeptideÀthymidine and Àuridine derivatives 8a ± 8d, 13a ± d, and 18 had a mild affinity with the polyA ¥ polyU duplex and could induce the change of RNA conformation. The results also implied that the interaction of conjugates with RNA might be related to the sugar pucker conformation of the nucleoside.Introduction. ± The functional and structural diversities of RNA provide numerous opportunities for academic researchers and pharmaceutical industry to develop small molecules to target specific RNA for treating a variety of diseases, such as bacteria or virus infections [1]. The RNA secondary structure of base pairing is more conservative than its primary sequence, so the potential for slower development of drug resistance against small molecules is one of the advantages of targeting RNA over traditional protein targets. Aminoglycosides, a class of structurally diverse aminocyclitols with potent antibiotic and antiviral activities are intensively and well-studied RNA binders. They can selectively and stoichiometrically bind with functional RNA motifs and disrupt the proteinÀRNA, RNPÀRNA, or RNAÀRNA interaction [2]. On the basis of the study of RNA in the presence of aminoglycosides and other small molecules, the interactions of RNA with small molecules are affected by the distribution of charged, aromatic, and H-bonding groups of a relatively rigid scaffold [1]. Considering the interaction of proteinÀRNA, the a-helix conformation of the protein provides a scaffold for H-bonding with RNA bases, the b-sheet form is suitable for binding aromatic groups with unstacked bases, and the negative phosphodiester moiety of RNA supplies a function for the electrostatic interaction. Furthermore, the structure of RNA is dynamic, and the conformational change can be induced by a small molecule [2]. The structural and functional features of RNA stimulated our enthusiasm to find moreselective and potent small molecules, and the adoption of virtual screening, surface plasmon resonance (SPR), and other technologies also speeded up the process [3].Our previous findings indicated that aminoglycosyl-nucleosides could bind to RNA with high affinity [4]. Besides that the configuration of the glycosyl moiety could affect their interaction, the heterocyclic-base moiety also showed an effect on the base stacking of the RNA duplex. Peptides have a relatively flexible conformation as compared to a glycosyl moiety. The diverse functional groups of a peptide, such as

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“…In order to gain more insight into the binding mechanism of SAH analogues on methylases, 5'-(/S-Lasparaginyl)-5'-deoxyadenosine (20a) and 5'-^-L-glutaminyl)-5'-deoxyadenosine (20b), in which an amide linkage replaced the thioether of SAH, were synthesized. The 5'-aminoacyl nucleosides are expected to have considerable stability as indicated by Robins et al,33 and the asparaginyl and glutaminyl chains incorporate the necessary points of attachment of the terminal -amino acid moiety to the methylases. Appropriately blocked asparatic acid and glutamic acid were coupled to the S'-amino group of 6 by the active ester method33 as shown in Scheme IV.…”

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confidence: 99%

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

Chang¹,

Coward²

1976

J. Med. Chem.

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The synthesis of S-adenosylhomocysteine analogues, in which the 5'-thioether linkage is replaced by an oxygen or nitrogen isostere, has been investigated. These compounds were disigned to be resistant to enzyme-catalyzed hydrolytic cleavage of the 5'-substituent. The amine analogue Id and two amide analogues 20 were prepared via alkylation or acylation of appropriately blocked adenosine derivatives. These new analogues were evaluated as inhibitors of catechol O-methyltransferase and tRNA methylases and found to have poor inhibitory activity.

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Nucleoside peptides. I. Synthesis of 5'-deoxy-5'amino-5'-N-aminoacyl peptide derivatives of guanosine, adenosine, and 2'-deoxyadenosine and their effect of cell-free protein synthesis

Cited by 14 publications

References 6 publications

Parallel Solution-Phase Synthesis of an Adenosine Antibiotic Analog Library

Parallel Solution-Phase Synthesis of an Adenosine Antibiotic Analog Library

Solid‐Phase Synthesis of Dipeptide‐Conjugated Nucleosides and Their Interaction with RNA

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

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