Analogs of (A2'p)nA. Correlation of structure of analogs of ppp(A2'p)2A and (A2'p)2A with stability and biological activity.

Eppstein, Deborah A.; March, Y V; Schryver, Brian; Larsen, M A; Barnett, Jimmy W.; Verheyden, Julien P. H.; Prisbe, Ernest J.

doi:10.1016/s0021-9258(18)33461-6

Cited by 60 publications

(11 citation statements)

References 54 publications

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“…Except for imidazolidate hydrolysis, no reaction proceeded between the 3'-deoxyadenosine derivative (22) and (14), whereas two products (18a and 21a) were generated in the reaction of the 2'-deoxyadenosine derivative (16) with MopA (14). When 3'-deoxyadenosine 5'-phosphoromorpholidate (23) was subjected to the usual Pb2+-catalysis conditions with ImpA (7), no coupling occurred even after 2 days incubation at 4 °C.…”

Section: Resultsmentioning

confidence: 99%

“…Next to be examined was the condensation of nucleotides of different heterocyclic bases (Scheme II). The reaction of MopA (14) with the 5'-phosphoroimidazolidate of inosine (ImpI, 17) gave MopA2'p5T (19a) as a major product in 21% yield, whereas reaction of the morpholidate of 5TMP (MopI, 15) with ImpA (7) gave MopI2'p5'A (20a) in 19% yield. The dinucleotides p5'I2'p5'A (20b) and p5'A2,p5'I (19b), obtained by acid hydrolysis of 20a and 19a, respectively, were completely resistant to degradation by either nuclease Px or RNase T2, but were completely digested with snake venom phosphodiesterase give p5T and p5'A in a 1:1 ratio (Table V).…”

Section: Resultsmentioning

confidence: 99%

“…Coupling of MopA (14) with Imp5'A2'p5'A (11c) thus produced Mop5'A2'p5'A2'p5'A (24, 18%) and Mop5'A3'p5'A2'p5'A (25, 8.8%) after DEAE-Sephadex chromatography. The structure of 24 was confirmed from its proton NMR spectrum (Table III) and by the fact that mild acid hydrolysis produced a product indistinguishable from authentic p5'A2'p5'A2'p5'A (la).…”

Section: Resultsmentioning

confidence: 99%

“…Lead ion catalyzed coupling was performed between MopA (14) and ImpA2'p5'(2'dA) (18c), between MopI (15) and ImpApA (17c), between MopA (14) and ' ' (19c) and between 14 and ImpA2'p5'I (20c) in a similar manner to that described for the above coupling of MopA and ImpApA (Scheme III, Table I). Yields of the desired all 2',5'-linked isomers (26,28,30,32) were in the range of 17-22% based on starting imidazolidate with accompanying quantities of the 3',5'-linkage isomers (27,29,31,33) in 8-11% yield.…”

Section: Resultsmentioning

confidence: 99%

“…Three bands appeared on the plates which were removed separately and the silica was extracted with acetone and stirred for 30 min and filtered. Removal of the solvent from band I gave ' (14) gave Mop5'a2'p5'A2'p5'I (30) in 17% yield. By acid hydrolysis, 30 could be converted to the corresponding 5'-monophosphate, or, by reaction with pyrophosphate in DMF, to the corresponding 2-5A analogue, ppp5'A2'p5'A2,p5,I (5b).…”

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Expedient chemical synthesis of sequence-specific 2',5'-oligonucleotides

Imai¹,

Torrence²

1985

J. Org. Chem.

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due to the presence of both a-and /3-isomers.] IR (CHC13) vm,, 3340 (NH, OH), 1730 (OCO), 1710 (COCH3), 1650 (7-pyrone), 1610, and 1585 cm™1 (Ar); MS (FAB), m/z (relative intensity) 731 (0.2, MH+), 730 (0.1, M+) 391 (0.1, O-sugar), 356 (0.8, MH+sugar), 355 (0.3, M+ -sugar), 340 [0.8, MH+ -(O-sugar)], 339 [1.8, M+ -(O-sugar)], 338 (0.9, 339 -H), 321 (1.2, 338 -OH), 320 (1.9, 338 -H20), ], 225 (2.8, 391 -C7H4N04), 122 (8.3, C6H4N02), 121 (100, 122 -H), 104 (15.3, C7H40).Mild Base Deprotection of 11 Affording the Glycosides 13 and 14. Compound 11 (85 mg) was dissolved in 15 mL of acetone, the solution was treated with 0.1 N NaOH (9 mL), and the reaction mixture was stirred for 30 min under a nitrogen atmosphere. The pH of the solution was adjusted to 8 by adding a few drops of 5% HC1 and the solution was then extracted with ethyl acetate (5 X 25 mL). The ethyl acetate extract was washed with water and dried (Na2S04). The solvent was removed under reduced pressure and the residue was dissolved in acetone and applied to preparative TLC plates and eluted with CHCl3-MeOH (4:1). Three bands appeared on the plates which were removed separately and the silica was extracted with acetone and stirred for 30 min and filtered. Removal of the solvent from band I gave ' (14) gave Mop5'a2'p5'A2'p5'I (30) in 17% yield. By acid hydrolysis, 30 could be converted to the corresponding 5'-monophosphate, or, by reaction with pyrophosphate in DMF, to the corresponding 2-5A analogue, ppp5'A2'p5'A2,p5,I (5b). The following oligonucleotides were prepared by using similar methodology: ppp5,A2,p5,A2'p5'A (lb), ppp5'A2'p5T2,p5'A (4b), ppp5T2,p5'A2,p5'A (3b), and ppp5'A2,p5'A2'p5' (2'dA) (2b).The natural occurrence of the 2,,5'-phosphodiester bond in S'-triphosphoryladenylyl^'-i-SOadenylyl^'-»-5)adenosine (2-5Á or 2',5'-oligo A), a mediator of interferon action,2 *™4 and in pre-tRNA,6 has led to increased interest 24 (trimethylammonium salt),

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Expedient chemical synthesis of sequence-specific 2',5'-oligonucleotides

Imai¹,

Torrence²

1985

J. Org. Chem.

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Nucleotides. Part XXVIII. Chemical syntheses of the 2′‐5′‐cordycepin‐trimer core

Charubala

Uhlmann

Himmelsbach

et al. 1987

Helvetica Chimica Acta

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The chemical synthesis of 3′‐deoxyadenyly‐(2′‐5′)‐3′‐deoxyadenylyl‐(2′‐5′)‐3′‐deoxyadenosine (30; trimeric cordycepin) is described by three different routes using various protecting groups and applying the phosphotriester approach. The intermediates have been isolated and characterized by elemental analyses and spectroscopic means. High yields of 30 have been obtained on deprotection making this biologically very active compound available in preparative scale.

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Nucleotides. Part XXXVIII.. Syntheses and characterization of phosphorothioate analogues of (2′–5′) adenylate dimer and trimer and their 5′‐O‐monophosphates

Charubala

Pfleiderer

1992

Helvetica Chimica Acta

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Dedicated to Prof. Dr. Wilhelm Fleischhacker on the occasion of his 60th birthday (8.X1.91) ~ ~~The chemical syntheses of the phosphorothioate of (2'-5')adenylate dimer (see 6a, 6b) and trimer (see 1 la, 1 lb, 12a, 12b) as well as of their 5'-monophosphates (see 15a, 15b, 16a, 16b) using the phosphoramidite method are described. The resulting diastereoisomer mixtures were separated into the pure components by chromatographical means. All synthetic intermediates were characterized by TLC, elemental analysis, and UV and 'H-NMR spectra.1. Introduction. -Establishment of an antiviral state in cells results from a multitude of biochemical changes induced by interferons and involving several proteins in a cascade of reactions [2-41. One of the proteins is the enzyme 2'-5'A synthetase, which is activated upon binding to double-stranded RNA [5] and converts then ATP into a series of (2'-5')-linked adenylate oligonucleotides containing a 5'-terminal triphosphate function [6]. Such oligomers carrying a 5'-di-or 5'-triphosphate and consisting of three or more monomer units bind to, and subsequently reversibly activate, an endogenous or sometimes interferon-induced endoribonuclease [7] [8]. The activated endoribonuclease, RNase L, cleaves then messenger and ribosomal RNA's [9], resulting in inhibition of translation. This effect, however, is only transitory, since the 2'-5'A molecules are rapidly cleaved by cellular phosphodiesterases [lo] leading to loss of antiviral activity. In order to suppress the digestion of the 2'-5'A oligomers, several synthetic modifications of the native structure were accomplished at the aglycone [ll-201, the sugar [21-371, and the phosphate moiety [38][39][40][41][42][43][44][45]. It is well established, mainly due to the pioneering work of Eckstein [46], that phosphorothioate analogues of oligonucleotides are valuable models to study certain stereochemical aspects of enzyme-catalyzed phosphoryl and nucleotidyl transfer reactions.The first synthesis of phosphorothioate analogues of (2'-5')oligoadenylates were performed by Nelson, Bach, and Verheyden [42] applying the phosphite triester approach in conjunction with sulfur oxidation. Formation of chiral phosphorothioate functions led to diastereoisomeric mixtures of which the dimer cores could be separated chromato-

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Analogs of (A2'p)nA. Correlation of structure of analogs of ppp(A2'p)2A and (A2'p)2A with stability and biological activity.

Cited by 60 publications

References 54 publications

Expedient chemical synthesis of sequence-specific 2',5'-oligonucleotides

Expedient chemical synthesis of sequence-specific 2',5'-oligonucleotides

Nucleotides. Part XXVIII. Chemical syntheses of the 2′‐5′‐cordycepin‐trimer core

Nucleotides. Part XXXVIII.. Syntheses and characterization of phosphorothioate analogues of (2′–5′) adenylate dimer and trimer and their 5′‐O‐monophosphates

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