Effects of the chiral isomers of erythro- and threo-9-(2-hydroxy-3-nonyl)adenine on purine metabolism in sarcoma 180 cells

Chen, Shih-Fong; Stoeckler, Johanna D.; Choi, Hye‐Seon; Burgess, Frederick W.; Marcaccio, Edward J.; Steen, Patricia A.; Berman, Susan F.; Parks, Robert E.; Panzica, Raymond P.; Abushanab, Elie

doi:10.1016/0006-2952(82)90641-4

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…We blocked adenosine deaminase (ADA), the enzyme that converts adenosine to inosine within the cells, with pharmacological inhibitor EHNA [18, 19]. As expected, EHNA did not reduce the protective effect of inosine or glucose but significantly decreased the viability of the adenosine treated cells subjected to OGD and also significantly increased the LDH release from the cells (Fig.…”

Section: Resultsmentioning

confidence: 88%

Identification of agents that reduce renal hypoxia–reoxygenation injury using cell-based screening: Purine nucleosides are alternative energy sources in LLC-PK1 cells during hypoxia

Szoleczky

Módis

Nagy

et al. 2012

Archives of Biochemistry and Biophysics

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Acute tubular necrosis is a clinical problem that lacks specific therapy and is characterized by high mortality rate. The ischemic renal injury affects the proximal tubule cells causing dysfunction and cell death after severe hypoperfusion. We utilized a cell-based screening approach in a hypoxia-reoxygenation model of tubular injury to search for cytoprotective action using a library of pharmacologically active compounds. Oxygen-glucose deprivation (OGD) induced ATP depletion, suppressed aerobic and anaerobic metabolism, increased the permeability of the monolayer, caused poly(ADP-ribose) polymerase cleavage and caspase-dependent cell death. The only compound that proved cytoprotective either applied prior to the hypoxia induction or during the reoxygenation was adenosine. The protective effect of adenosine required the coordinated actions of adenosine deaminase and adenosine kinase, but did not requisite the purine receptors. Adenosine and inosine better preserved the cellular ATP content during ischemia than equimolar amount of glucose, and accelerated the restoration of the cellular ATP pool following the OGD. Our results suggest that radical changes occur in the cellular metabolism to respond to the energy demand during and following hypoxia, which include the use of nucleosides as an essential energy source. Thus purine nucleoside supplementation holds promise in the treatment of acute renal failure.

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Section: Resultsmentioning

confidence: 88%

Identification of agents that reduce renal hypoxia–reoxygenation injury using cell-based screening: Purine nucleosides are alternative energy sources in LLC-PK1 cells during hypoxia

Szoleczky

Módis

Nagy

et al. 2012

Archives of Biochemistry and Biophysics

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“…Anal. 9-[l-Fluoro-2(fl)-octyl]adenine (23). To a cold (-78 °C) solution of (diethylamido)sulfur trifluoride (DAST, 0.15 mL, 1.14 mmol) in CH2C12 (3 mL) was slowly added a solution of 22 (113 mg, 0.430 mmol) in anhydrous CH2C12 (3 mL), and stirring was continued for 1 h. After stirring for 1 h at room temperature, excess DAST was decomposed by the careful addition of cold saturated solution of NaHC03 (5 mL).…”

Section: -[L^(sf)-(isopropylidenedioxy)-3(fi)-nonyl]adenine(13)mentioning

confidence: 99%

“…(13) Gieger, J. D.; Lewis, J. L.; MacIntyre, C. J.; Nagy, J. (+)-EHNA (+)-2S,3fi isomer as the most potent ADA inhibitor.21 (+)-EHNA proved to be the most active isomer in the enhancement of oro-A activity against human pancreatic and colon carcinomas.22 All four stereoisomers caused similar inhibition of purine biosynthesis in sarcoma 180 cells, but these effects were not pronounced below drug concentrations of 1 x 10~* ***5 M. 23 The comparable anti-HSV activity of all four isomers suggests that the antiviral activity is not mediated through inhibition of ADA. 24 Recently, an apparent isoenzyme of ADA had been identified, ADA2.…”

Section: Introductionmentioning

confidence: 99%

Adenosine deaminase inhibitors. Synthesis and biological evaluation of C1' and nor-C1' derivatives of (+)-erythro-9-[2(S)-hydroxy-3(R)-nonyl]adenine

Harriman¹,

Poirot²,

Abushanab³

et al. 1992

J. Med. Chem.

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The synthesis of various chiral derivatives of (+)-erythro-9-(2-hydroxy-3-nonyl)adenine, (+)-EHNA, from (2S,3R)-3-amino-1,2-O-isopropylidene-1,2-nonanediol by condensation with 5-amino-4,6-dichloropyrimidine is described. The compounds synthesized were C1'- and nor-C1'-(+)-EHNA derivatives. When tested with calf spleen ADA, C1'-OH- and nor-C1'-(+)-EHNA had comparable inhibitory activity that was 1 order of magnitude lower than that of (+)-EHNA. Potency was reduced further in nor-C1' derivatives.

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Effects of chirality in 9-(2-hydroxy-3-nonyl)adenine upon deoxyribonucleic acid synthesis in herpes simplex virus-infected cells

North

O'Connor

Abushanab

et al. 1983

Biochemical Pharmacology

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Effects of the chiral isomers of erythro- and threo-9-(2-hydroxy-3-nonyl)adenine on purine metabolism in sarcoma 180 cells

Cited by 4 publications

References 14 publications

Identification of agents that reduce renal hypoxia–reoxygenation injury using cell-based screening: Purine nucleosides are alternative energy sources in LLC-PK1 cells during hypoxia

Identification of agents that reduce renal hypoxia–reoxygenation injury using cell-based screening: Purine nucleosides are alternative energy sources in LLC-PK1 cells during hypoxia

Adenosine deaminase inhibitors. Synthesis and biological evaluation of C1' and nor-C1' derivatives of (+)-erythro-9-[2(S)-hydroxy-3(R)-nonyl]adenine

Effects of chirality in 9-(2-hydroxy-3-nonyl)adenine upon deoxyribonucleic acid synthesis in herpes simplex virus-infected cells

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