Amniotic fluid levels of 21-deoxycortisol (21-DOF) and 17-hydroxyprogesterone (17-OHP) were measured in 49 pregnancies, including 31 pregnancies at risk for CAH. The results were compared with those obtained by HLA typing and linkage analysis to a HLA DNA probe. The mean amniotic fluid levels in the control pregnancies were 0.28 nmol/L for 21-DOF and 4.1 nmol/L for 17-OHP. The levels were similar in early and midpregnancy for 21-DOF (0.29 vs. 0.27 nmol/L) and 17-OHP (3.4 vs. 4.2 nmol/L). The amniotic fluid 21-DOF level was 1.75 nmol/L in affected pregnancies, significantly higher than in the control pregnancies (mean, 0.28 nmol/L). The mean amniotic fluid 17-OHP level in the affected pregnancies (30.5 nmol/L) also was significantly higher than that in the control pregnancies (4.10 nmol/L). Simultaneous measurement of 21-DOF and 17-OHP levels in amniotic fluid from 10-18 weeks of gestation can be used for early diagnosis of congenital adrenal hyperplasia.
Charakteristisch für Pyrrolamid-Naturstoffe ist eine Pyrrol-2-carboxamid-Einheit. In Fütterungsexperimenten mit Streptomyces ambofaciens wurde 4-Acetamidopyrrol-2-carboxylat als die entscheidende Pyrrolamid-Vorstufe von Congocidin identifiziert (siehe Schema). Die Biosynthese von Congocidin geht von N-Acetylglucosamin aus und verläuft unter Beteiligung von Enzymen, die Kohlenhydrate umsetzen.
Neuroblastoma (NB), the most frequent extracranial solid tumor of children accounting for nearly 15% of all childhood cancer mortality, displays overexpression of antiapoptotic Bcl-2 and Mcl-1 in aggressive forms of the disease. The clinical phase 2 drug roscovitine (CYC202, seliciclib), a relatively selective inhibitor of cyclin-dependent kinases (CDKs), and CR8, a recently developed and more potent analog, induce concentration-dependent apoptotic cell death of NB cells (average IC50 values: 24.2 µM and 0.4 µM for roscovitine and CR8, respectively). Both roscovitine and CR8 trigger rapid down-regulation of the short-lived survival factor Mcl-1 in the 9 investigated human NB cell lines. This effect was further analyzed in the human SH-SY5Y NB cell line. Down-regulation of Mcl-1 appears to depend on inhibition of CDKs rather than on interaction of roscovitine and CR8 with their secondary targets. CR8 is an adenosine triphosphate-competitive inhibitor of CDK9, and the structure of a CDK9/cyclin T/CR8 complex is described. Mcl-1 down-regulation occurs both at the mRNA and protein levels. This effect can be accounted for by a reduction in Mcl-1 protein synthesis, under stable Mcl-1 degradation conditions. Mcl-1 down-regulation is accompanied by a transient increase in free Noxa, a proapoptotic factor. Mcl-1 down-regulation occurs independently of the presence or up-regulation of p53 and of the MYCN status. Taken together, these results suggest that the clinical drug roscovitine and its novel analog CR8 induce apoptotic tumor cell death by down-regulating Mcl-1, a key survival factor expressed in all NB cell lines. CDK inhibition may thus constitute a new approach to treat refractory high-risk NB.
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Plasma 21-deoxycortisol (21-DOF) and 17-hydroxyprogesterone (17-OHP) concentrations were assayed before (basal) and 1 h after ACTH stimulation in 4 groups of normal subjects (35 follicular phase women, 22 luteal phase women, 33 adult men, and 15 prepubertal children) and in a group of 31 patients with the late-onset form of congenital adrenal hyperplasia (LOCAH) due to 21-hydroxylase deficiency as well as in 31 LOCAH heterozygotes. The mean basal plasma 21-DOF concentrations in each of the 4 groups of normal subjects were between 8 ng/dL (0.23 nmol/L) and 11 ng/dL (0.31 nmol/L), and they increased significantly after ACTH stimulation to between 36 ng/dL (1.04 nmol/L) and 44 ng/dL (1.27 nmol/L). There were no differences in basal or ACTH-stimulated plasma 21-DOF levels in these 4 groups, whereas their basal and post-ACTH plasma 17-OHP levels did vary. Among the LOCAH patients, 83.8% had basal plasma 21-DOF levels and 61.2% had basal plasma 17-OHP levels higher than the highest basal 21-DOF [30 ng/dL (0.86 nmol/L)] and 17-OHP [450 ng/dL (13.61 nmol/L)] concentrations in the normal subjects, and all individual 21-DOF and 17-OHP levels after ACTH stimulation [≥404 ng/dL (11.67 nmol/L) and ≥1040 ng/dL (31.47 nmol/L), respectively] were markedly higher than thehighest 21-DOF [76 ng/dL (2.19 nmol/L)] and 17-OHP [580 ng/ dL (17.55 nmol/L)] levels in the normal subjects. The mean post-ACTH/basal plasma level ratios among the LOCAH patients were 19.75 for 21-DOF and 8.03 for 17-OHP. In LOCAH heterozygotes, basal 21-DOF values were higher than normal in 48.3%, and post-ACTH values were higher than normal in 93.5% of the cases. In contrast, basal plasma 17-OHP levels were similar in LOCAH heterozygotes and normal subjects, and only 16.1% of the LOCAH heterozygotes had post-ACTH plasma 17- OHP levels higher than the highest normal value. If sex and phase of the menstrual cycle are taken into account, along with the incremental responses (post-ACTH minus baseline value) of plasma 21-DOF and 17-OHP, to compare LOCAH heterozygotes and normal subjects, the discriminating power for detection of heterozygocity was somewhat increased for 21-DOF (to 100%) and appreciably increased for 17-OHP (to 30%). However, the post-ACTH 21-DOF level and the incremental response, regardless of whether age, sex, and menstrual cycle phase were taken into account, led to the detection of more than 90% of the LOCAH heterozygotes, thus suggesting that 21-DOF is a better marker than 17-OHP for diagnosing LOCAH heterozygotes.
The action of sodium cyanide ongem -diphenyl-chloropropanone under phase transfer conditions in the presence of 15-crown-5 yields the title compound as a minor product. The crystal structure of this complex reveals that, in the solid state, the [15-crown-5-Na+] guest species is found within a loose cage of diphenylethyl diphenyl cyanoacetonate molecules with one open side of the cage blocked by an adjacent 15-crown-5 molecule. Colourless crystals of the compound belong to the monoclinic space groupP21/n witha = 12,255(2) A,b = 13,005(1) A,c = 23,433(2) A, β = 95,92(1) ° andD
c = 1.23 g cm−3 forZ = 4.
A number of drugs active against prions either in vitro, in cellular systems or in vivo in animal models have been isolated in various screening assays. In this minireview, we would like to suggest, that in addition to their direct interest as potential therapeutic agents, these molecules could be used as original research tools to understand prion propagation. The use of antiprion compounds as tool to understand fundamentals of prion propagation relies on reverse screening approaches. These global genetic and/or biochemical approaches aim to identify the intracellular target(s) and mechanism of action of the drugs. Once those are known, the biological activity of the compounds can be optimized on a rational basis, their potential side effects understood and minimized. In vitro enzyme-based screening assays can then be designed to allow discovery of new, more potent and selective molecules. Here we describe the main comprehensive biochemical and genetical approaches to realize reverse screening approaches based on antiprion drugs. We will finish by discussing the interest of using drug inactivation of specific targets as a substitute to genetic inactivation.
