60129-59-1Relevant academic research and scientific papers
4'-SUBSTITUTED NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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Page/Page column 30; 31; 32, (2015/12/08)
Provided is 4'-substituted nucleoside derivatives of Formula I and their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC.
Influence of the nucleobase and anchimeric assistance of the carboxyl acid groups in the hydrolysis of amino acid nucleoside phosphoramidates
Maiti, Munmun,Michielssens, Servaas,Dyubankova, Natalia,Maiti, Mohitosh,Lescrinier, Eveline,Ceulemans, Arnout,Herdewijn, Piet
supporting information; experimental part, p. 857 - 868 (2012/03/26)
Nucleoside phosphoramidates (NPs) are a class of nucleotide analogues that has been developed as potential antiviral/antitumor prodrugs. Recently, we have shown that some amino acid nucleoside phosphoramidates (aaNPs) can act as substrates for viral polymerases like HIV-1 RT. Herein, we report the synthesis and hydrolysis of a series of new aaNPs, containing either natural or modified nucleobases to define the basis for their differential reactivity. Aqueous stability, kinetics, and hydrolysis pathways were studied by NMR spectroscopy at different solution pD values (5-7) and temperatures. It was observed that the kinetics and mechanism (P-N and/or P-O bond cleavage) of the hydrolysis reaction largely depend on the nature of the nucleobase and amino acid moieties. Aspartyl NPs were found to be more reactive than Gly or β-Ala NPs. For aspartyl NPs, the order of reactivity of the nucleobase was 1-deazaadenine>7- deazaadenine>adenine>thymine≥3-deazaadenine. Notably, neutral aqueous solutions of Asp-1-deaza-dAMP degraded spontaneously even at 4°C through exclusive P-O bond hydrolysis (a 50-fold reactivity difference for Asp-1-deaza-dAMP vs. Asp-3-deaza-dAMP at pD 5 and 70°C). Conformational studies by NMR spectroscopy and molecular modeling suggest the involvement of the protonated N3 atom in adenine and 1- and 7-deazaadenine in the intramolecular catalysis of the hydrolysis reaction through the rare syn conformation. Touching (nucleo)base: A dual intramolecular catalytic influence is demonstrated by the nucleobase and carboxyl groups in the chemical hydrolysis of amino acid nucleoside phosphoramidate prodrugs (see scheme). The replacement of the adenine N1 or N7 atoms instead of the N3 atom is shown to have a conformational role in which the protonated N3 is crucial in regulating the kinetics and mechanism of nucleotide (P-N pathway) versus nucleoside (P-O pathway) formation. Copyright
Chemoenzymatic synthesis of 7-deaza cyclic adenosine 5′-diphosphate ribose analogues, membrane-permeant modulators of intracellular calcium release
Zhang, Bo,Bailey, Victoria C.,Potter, Barry V. L.
, p. 1693 - 1703 (2008/09/20)
(Chemical Equation Presented) An optimized synthetic route to 7-deaza-8-bromo-cyclic adenosine 5′-diphosphate ribose (7-deaza-8-bromo-cADPR 3), an established cell-permeant, hydrolysis-resistant cyclic adenosine 5′-diphosphate ribose (cADPR) antagonist, i
Incorporation of 2'-deoxysangivamycin in DNA duplexes: The conversion of a pyrrolo[2,3-d]pyrimidine nitrile to a carboxamide upon oligonucleotide deprotection
Seela, Frank,Zulauf, Matthias
, p. 2697 - 2709 (2007/10/03)
Oligonucleotides containing 2'-deoxysangivamycin are described. The phosphoramidite of 2'-deoxytoyocamycin was prepared and used in solid-phase synthesis. Upon deprotection the pyrrolo[2,3-d]pyrimidine nitrile residues were converted to carboxamides. Acco
8. Duplex stabilization of DNA: Oligonucleotides containing 7-substituted 7-deazaadenines
Seela,Thomas
, p. 94 - 108 (2007/10/02)
The oligonucleotide building blocks 4b-d derived from 7-bromo-, 7-chloro-, and 7-methyl-substituted 7-deaza-2'-deoxyadenosines 3b-d were prepared. They were employed in the solid-phase synthesis of the oligonucleotides 7-25. The dA residues of the homomer d(A12), the alternating d[(A-T)6], and the palindromic d(G-T-A-G-A-A-T-T-C-T-A-C) were replaced by 3b-d as well as by the parent 7-deaza-2'-deoxyadenosine (3a). The melting profiles and CD spectra of oligonucleotide duplexes, showing this major groove modification, were measured, and the T(m) values as well as the thermodynamic data were determined. It was found that small substituents such as Br, Cl, or Me introduced in the 7-position of a 7-deazaadenine residue increase the duplex stability compared to oligonucleotides containing adenine.
Synthesis and Biological Activity of Certain 6-Substituted and 2,6-Disubstituted 2'-Deoxyturbercidins Prepared via the Stereospecific Sodium Salt Glycosylation Procedure
Cottam, Howard B.,Kazimierczuk, Zygmunt,Geary, Stewart,McKernan, Patricia A.,Revankar, Ganapathi R.,Robins, Roland K.
, p. 1461 - 1467 (2007/10/02)
A number of 6-substituted and 2,6-disubstituted pyrrolopyrimidine 2'-deoxyribonucleosides were prepared by the direct stereospecific sodium salt glycosylation procedure.Reaction of the sodium salt of 4-chloro-6-methyl-2-(methylthio)pyrrolopyrimidine (6a) or 4,6-dichloro-2-(methylthio)pyrrolopyrimidine (6b) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose (9) provided the corresponding N7 2'-deoxy-β-D-ribofuranosyl blocked derivatives (8a and 8c) which, on ammonolysis, gave 4-amino-6-methyl-2-(methylthio)-7-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyrimidine (11a) and 4-amino-6-chloro-2-(methylthio)-7-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyrimidine (11b), respectively.Dethiation of 11a and 11b afforded 6-methyl-2'-deoxytubercidin (10a) and 6-chloro-2'-deoxytubercidin (10b), respectively.Dehalogenation of 10b provided an alternate route to the reported 2'-deoxytubercidin (3a).Application of this glycosylation procedure to 4,6-dichloro and 4,6-dichloro-2-methyl derivatives of pyrrolopyrimidine (15a and 15b) gave the corresponding blocked 2'-deoxyribonucleosides (18a and 18b), which on ammonolysis furnished 10b and 4-amino-6-chloro-2-methyl-7-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyrimidine (17), respectively.This stereospecific attachment of the 2-deoxy-β-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C1 carbon by the anionic heterocyclic nitrogen.Controlled deacylation of 4-chloro-7-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)pyrrolopyrimidine (20a) gave 4-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyrimidine (20b).Dehalogenation of 20b gave the 2'-deoxynebularin analogue 7-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyrimidine (19), and reaction of 20b with thiourea gave 7-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyrimidine-4(3H)-thione (21).All of these compounds were tested in vitro against certain viruses and tumor cells.Only compounds 12a, 20b, and 21 showed significant activity against measles in vitro, and the activity is comparable to that of ribavirin.Although compounds 3a and 12b are slightly more active than ribavirin against HSV-2 in vitro, they are relatively more toxic to Vero cells.Compounds 3a and 20b exhibited moderate cytostatic ativity against L1210 and P388 leukemia in vitro but are considerably less active than 2-chloro-2'-deoxyadenosine (1).
Synthesis of 2'-Deoxytubercidin, 2'-Deoxyadenosine, and Related 2'-Deoxynucleosides via a Novel Direct Stereospecific Sodium Salt Glycosylation Procedure
Kazimierczuk, Zygmunt,Cottam, Howard B.,Revankar, Ganapathi R.,Robins, Roland K.
, p. 6379 - 6382 (2007/10/02)
A general and stereospecific synthesis has been developed for the direct preparation of 2'-deoxy-β-D-ribofuranosylpurine analogues including 2'-deoxyadenosine derivatives.The reaction of the sodium salt of 4-chloropyrrolopyrimidine (4) or 2,4-dichloropyrrolopyrimidine (1) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose (25) provided the corresponding N-1,2'-deoxy-β-D-ribofuranosyl blocked derivatives (5 and 2) which, on ammonolysis, gave 2'-deoxytubercidin (6) and 2-chloro-2'-deoxytubercidin (3), respectively, in good yield.This glycosylation also readily proceeds in the presence of a 2-methylthio group.Application of this glycosylation procedure to 4,6-dichloroimidazopyridine (10), 6-chloropurine (16), 2,6-dichloropurine (13), and 4-chloropyrazolopyrimidine (19) gave 2-chloro-2'-deoxy-3-deazaadenosine (12), 2-'-deoxyadenosine (18), 2-chloro-2'-deoxyadenosine (15), and 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrazolopyrimidine (21), respectively.Similarly, glycosylation and ammonolysis of 4,6-dichloro-1H-pyrrolopyridine (22) gave 4,6-dichloro-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyridine (24).This stereospecific attachment of the 2-deoxy-β-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C-1 carbon of 25.
NUCLEIC ACID RELATED COMPOUNDS. 42. A GENERAL PROCEDURE FOR THE EFFICIENT DEOXYGENATION OF SECONDARY ALCOHOLS. REGIOSPECIFIC AND STEREOSELECTIVE CONVERSION OF RIBONUCLEOSIDES TO 2 prime -DEOXYNUCLEOSIDES.
Robins,Wilson,Hansske
, p. 4059 - 4065 (2007/10/02)
Treatment of unhindered secondary alcohols with phenoxythiocarbonyl chloride (phenyl chlorothionocarbonate) in pyridine/dichloromethane, or in acetonitrile with 4-dimethylaminopyridine catalysis for hindered alcohols, gave clean conversion to their O-phenoxythiocarbonyl derivatives. Reductive deoxygenation of these phenyl thionocarbonate esters proceeded smoothly, using tri-n-butyltin hydride and a free radical initiator in warm toluene. Overall conversion yields ranged from 57 to 78% for the naturally occurring nucleosides, nucleoside antibiotics, and methyl beta -D-ribofuranoside.
