Purification and Properties of Adenosine Kinase from Human Tumor Cells of Type H. Ep. No. 2

Schnebli, Hans Peter; Hill, Donald L.; Bennett, L. Lee

doi:10.1016/s0021-9258(18)96008-4

Cited by 167 publications

(20 citation statements)

References 42 publications

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“…(CnH13FN404S) C, , N. 9-(2,3,5-Tri-0-acetyl-/3-D-ribofuranosyl)-2-fluoro-A7-hydroxyadenine (9).-A solution (3 ml, 0.5 N) of HONH2 in EtOH was added to a solution of 9-(2,3,5-tri-0-acetyl-/3-D-ribofuranosyl)-2.6-difluoropurine17 (6, 800 mg, 1.9 mmol) in EtOH (10 ml, dried over Linde 3A sieve), and the solution was stirred under X2 at 5°for 10 min before a second addition of 0.5 N HONH2 in EtOH (4 ml). The reaction mixture was stirred for an additional hour before it was evaporated to dryness in vacuo (10)(11)(12)(13)(14)(15) mm/25°). The residue was triturated with EtOAc (10 ml), filtered, and the filtrate evaporated to dryness in vacuo.…”

Section: Methodsmentioning

confidence: 99%

“…The triacetate of 2,6-difluoro-9-j3-i)-ribofuranosylpurme showed moderate cytotoxicity. 2-Fluoro-A7-methyladenosine (11) 23 2-Fluoro-A7,A7-dimethyladenosine (12) >130 A-Hydroxvadenosine 32 2-Fluoro-A7-hydroxyadenosine triacetate (9) 0.97 A7-Aminoadenosine 1.8 Ar-Amino-2-fluoroadenosine triacetate (10) 6.7 2-Fluoro-6-(methylthio)purine ribonucleoside (5) 19 6-(Methylthio)purine ribonucleoside 0.30 2,6-Difluoropurine ribonucleoside triacetate (6) 31 " Human epidermoid carcinoma cells No. 2.…”

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confidence: 99%

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2-Fluoropurine ribonucleosides

Hewson¹

1970

J. Med. Chem.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

2-Fluoropurine ribonucleosides

Hewson¹

1970

J. Med. Chem.

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“…A solution of NaOMe (81 mg, 1.50 mmol) in MeOH (60 ml) was saturated with MeSH, treated with a solution of 2 (874 mg, 2.00 mmol) in CHCI3 (20 ml), allowed to stand in a stoppered flask for 66 h, diluted with H20 (80 ml), and neutralized with Amberlite IR-120 H+ ion-exchange resin. The aqueous layer was washed with CHCI3 and evaporated to dryness in vacuo, and the residue was crystallized from EtOH and dried in vacuo (P2O5): yield 224 mg (50%); mp 150 °C; Xmax nm (t X 10-3) (EtOH) (0.1 N HC1) 226 (10.5), 304 (14.5), (pH 7) 226 (10.5), 303 (14.4); XH NMR 2.79 (s, 3, CH:;), 3.58 (m, 2, Hr-), 4.06 (m, 1, Hr), 4.39 (m, 1, H3), 4.83 (m, 2, OrH, H2), 5.27 (d, 1, 02H), 5.59 (d, 1, 3 ), 6.29 (d, 1, Jr 2 = 5.0 Hz, Hr), 8.97 (s, 1, Hr). Anal.…”

Section: Methodsmentioning

confidence: 99%

Analogs of 8-azainosine

Elliott¹

1977

J. Med. Chem.

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A convenient synthesis of 8-azapurine ribonucleosides substituted at the 6 position with thio, alkylthio, alkoxy, amino, and alkylamino groups is described. The reaction of 6-(methylthio)-8-azapurine (1) with 2,3,5-tri-O-acetyl-D-ribofuranosyl chloride in the presence of Linde AW-500 molecular sieve gave a 2:1 mixture of 2 and 3, respectively. This mixture was rearranged by heating with molecular sieve in refluxing toluene to give a 6:1 mixture of 2 and 3. Treatment of 2 or 3 with the appropriate nucleophiles at room temperature gave 6-substituted 8-azapurine ribonucleosides (7-substituted 2- or 3-beta-D-ribofuranosyl-3H-1,2,3-triazolo[4,5-d]pyrimidines) 4-13. The thione 11 rearranges to N-beta-D-ribofuranosyl[1,2,3]thiadiazolo[5,4-d]pyrimidin-7-amine (14) in the solid state or in solution. All of these compounds were cytotoxic to H.Ep. No. 2 cells in culture except the parent base, 8-aza-6-(methylthio)purine (1) and the 8-isomers (3,12, and 13). Three of these compounds-8azaadenosine (4), 8-aza-6-(methylthio)purine ribonucleoside (5), and 8-aza-6-(methoxy)purine ribonucleoside (7)-showed borderline activity in the leukemia L1210 system. The thiadiazolopyrimidine (14) showed activity at three dose levels.

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“…GS-441524 differs from adenosine by having C substituted with N at position 4, and substitutions of N with C at positions 7 and 9 in its adenine moiety, in addition to a cyano group linked to the 1′ position in the ribose part ( Figure 1 ). Previously, the adenosine analog tubercidine, in which N at position 7 of its adenine moiety is replaced with C, was reported to be more efficiently phosphorylated than adenosine by mammalian ADKs including human ADK, while substitution of N with C at position 9 led to reduced phosphorylation [ 74 , 75 ]. Moreover, psicofuranine, an antineoplastic and antibiotic adenosine analog with a 1′-hydroxymethyl group, but otherwise identical to adenosine, is not a substrate of rabbit ADK [ 76 ].…”

Section: Intracellular Adenosine Levelsmentioning

confidence: 99%

Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19

Rasmussen

Jürgens

Thomsen

et al. 2021

Viruses

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GS-441524 is an adenosine analog and the parent nucleoside of the prodrug remdesivir, which has received emergency approval for treatment of COVID-19. Recently, GS-441524 has been proposed to be effective in the treatment of COVID-19, perhaps even being superior to remdesivir for treatment of this disease. Evaluation of the clinical effectiveness of GS-441524 requires understanding of its uptake and intracellular conversion to GS-441524 triphosphate, the active antiviral substance. We here discuss the potential impact of these pharmacokinetic steps of GS-441524 on the formation of its active antiviral substance and effectiveness for treatment of COVID-19. Available protein expression data suggest that several adenosine transporters are expressed at only low levels in the epithelial cells lining the alveoli in the lungs, i.e., the alveolar cells or pneumocytes from healthy lungs. This may limit uptake of GS-441524. Importantly, cellular uptake of GS-441524 may be reduced during hypoxia and inflammation due to decreased expression of adenosine transporters. Similarly, hypoxia and inflammation may lead to reduced expression of adenosine kinase, which is believed to convert GS-441524 to GS-441524 monophosphate, the perceived rate-limiting step in the intracellular formation of GS-441524 triphosphate. Moreover, increases in extracellular and intracellular levels of adenosine, which may occur during critical illnesses, has the potential to competitively decrease cellular uptake and phosphorylation of GS-441524. Taken together, tissue hypoxia and severe inflammation in COVID-19 may lead to reduced uptake and phosphorylation of GS-441524 with lowered therapeutic effectiveness as a potential outcome. Hypoxia may be particularly critical to the ability of GS-441524 to eliminate SARS-CoV-2 from tissues with low basal expression of adenosine transporters, such as alveolar cells. This knowledge may also be relevant to treatments with other antiviral adenosine analogs and anticancer adenosine analogs as well.

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Purification and Properties of Adenosine Kinase from Human Tumor Cells of Type H. Ep. No. 2

Cited by 167 publications

References 42 publications

2-Fluoropurine ribonucleosides

2-Fluoropurine ribonucleosides

Analogs of 8-azainosine

Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19

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