Disease relevance of NSC55712

• After intranasal treatment with compound A, eosinophils in the lungs and their activation products were substantially decreased, documenting its effectiveness in inhibiting lung inflammation [1].
• In addition, shortterm application of compound A to rats suffering from traumatic brain injury induced by subdural hematoma resulted in a significant reduction of the cerebral infarct volume [2].
• There was a dose-dependent inhibition of eosinophilia in the bronchiolar lavage fluid, when compound A was given intranasally but not when it was given intravenously [1].
• These studies suggested that sevoflurane can result in renal toxicity, mediated by compound A, under specific circumstances [3].
• 9 Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed-type hypersensitivity [4].

High impact information on NSC55712

• Whereas 6 beta-hydroxycorticosterone did not upregulate angiotensin II receptor binding (a marker for corticosteroid action in vascular smooth muscle), compound A caused concentration-dependent upregulation [5].
• Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP [6].
• In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen [6].
• As shown by immunocytochemistry and immunoblotting, compound A inhibited NF-kappa B and AP-1 activity in mixed glial cultures [2].
• 1-Methyl-4-phenylpyridinium-induced damage of mesencephalic dopaminergic neurons was significantly decreased, and long-term treatment of 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine-injected mice with compound A significantly and dose-dependently reduced dopaminergic neuronal cell death [2].

Chemical compound and disease context of NSC55712

• The mechanism of compound A renal toxicity is controversial, with the debate focused on the role of the renal cysteine conjugate beta-lyase pathway in the biotransformation of compound A [3].
• Aminooxyacetic acid diminished compound A-dependent proteinuria and glucosuria but did not decrease necrosis [7].
• In in vivo rat assays, compound A inhibited acetylcholine-induced bronchoconstriction and bradycardia with intravenous ED(50) values of 0.022 mg/kg and >/=10 mg/kg, respectively [8].
• Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity [9].
• Dehydration of Baralyme increases compound A resulting from sevoflurane degradation in a standard anesthetic circuit used to anesthetize swine [10].

Biological context of NSC55712

• Therefore, if biotransformation by this pathway is responsible for the production of nephrotoxic metabolites of compound A, humans may be less susceptible to compound A renal toxicity than are rats [3].
• Areas under the inspired and expired compound A concentration versus time curves (AUC) were 79 +/- 54-ppm-h (range, 10-223 ppm-h) and 53 +/- 40 ppm-h (range, 6-159 ppm-h), respectively [11].
• Mean maximum inhalation concentration of compound A using baralyme was 20.28 +/- 8.6 ppm (mean +/- SEM) compared to 8.16 +/- 2.67 ppm obtained with soda lime, a difference that did not reach statistical significance [12].
• RESULTS: The lowest concentration of compound A applied without metabolic activator (27 ppm) significantly increased (P < 0.001) sister chromatid exchanges, and increasing concentrations of compound A increased the incidence of exchanges [13].
• RESULTS: During anesthesia, average and maximum inspired compound A concentrations were 27 +/- 7 and 34 +/- 6 (mean +/- SD) and median mean blood pressure, esophageal temperature, and end-tidal carbon dioxide levels were 63 mmHg, 36.8 degrees C, and 32 mmHg, respectively [14].

Anatomical context of NSC55712

• In this study, we show that a synthetic derivative of the natural product rocaglaol (compound A) displays potent anti-inflammatory properties in human endothelial and murine glial cells in vitro [2].
• Exposure of fibroblasts to 7,500 ppm of compound A for 1 h, compound A did not induce structural change [15].
• The inhibition of compound A (3 mg/kg i.v.) on ex vivo binding in rat cerebral cortex was almost similar to that of NMS [8].
• Collectively, these results suggest that compound A is a highly selective IP receptor antagonist that inhibits iloprost-induced sensitization of sensory neurons [16].
• 5 COMPOUND A inhibited stress-induced NF-kappaB transactivation, chemokine-, cytokine-, and adhesion molecule expression, and T- and B-cell proliferation [4].

Associations of NSC55712 with other chemical compounds

• Quantitative determination of vapor-phase compound A in sevoflurane anesthesia using gas chromatography-mass spectrometry [17].
• Both the "shallow" probe (compound A) and the "depth" probe (compound B) were coupled for 10-14% (of the label added) to apoA-I and apoA-II from HDL3 and for about 6% to apoA-I and apoA-II from HDL2 [18].
• These results suggest that binding of the test substances to CBG in female rat plasma and concomitant displacement of endogenous corticosterone could be part of the contraceptive mechanism of S. tuberculatiformis and the aziridine precursor, compound A [19].
• The results demonstrate that most of the reactive intermediates and products formed by the beta-lyase-catalyzed biotransformation of compound A-derived cysteine S-conjugates are also formed in the two chemical systems studied [20].
• The primary active transport previously assessed in an in vitro study in canalicular membrane vesicles was also highest for BQ-485 and lowest for compound A, similar to CLbile, h/fT in vivo [21].

Gene context of NSC55712

• For further characterization of ABCG2-mediated transport, we investigated indolocarbazole compound A (Fig. 1) excretion in cell-free system [22].
• In vitro cytochrome P450 (P450) reaction phenotyping of compound A revealed that the metabolism was catalyzed exclusively by CYP3A4 [23].
• 4 We identified COMPOUND A as a small-molecule, ATP-competitive inhibitor selectively targeting IKK-beta kinase activity with a K(i) value of 2 nM [4].
• 6 COMPOUND A is orally bioavailable and inhibited the release of LPS-induced TNF-alpha in rodents [4].
• It is concluded that the hydroxylation of compound A is mainly catalyzed by CYP2C8, and thus the reaction can possibly serve as an alternative marker assay for CYP2C8 in human liver microsomes [24].

Analytical, diagnostic and therapeutic context of NSC55712

• These results suggest that by inhibiting NF-kappa B and AP-1 signaling, compound A is able to reduce tissue inflammation and neuronal cell death, resulting in significant neuroprotection in animal models of neurodegeneration [2].
• In three studies in human volunteers and one in surgical patients, prolonged (8-hour) sevoflurane exposures and low fresh gas flow rates resulted in significant exposures to compound A [3].
• Frontal affinity chromatography (FAC) using immobilized polyclone antibodies of compound A coupled with mass spectrometry was used for the screening of affinity compounds from an extract of Phyllanthus urinaria L [25].
• The compound A concentration was measured by gas chromatography [26].
• Manipulation of the beta-lyase pathway elicited similar results, whether compound A was administered by inhalation or intraperitoneal injection [7].

References