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A purpose-built high-resolution array with 93.75% breakpoint accuracy was used to map 4000 patients with diverse diagnoses and identify eight probands harboring microdeletions at TP53 (17p13.1), a DNA copy-number variations (CNVs) which might cause childhood-onset developmental delay (DD) and cancer. The results revealed a possible association of 17p13.1 CNVs with distinct phenotypes depending on the position of the breakpoint with respect to TP53 and called for further studies to determine if other loci in the genome also give rise to phentotypically distinct disorder.

Abstract: A highly efficient and versatile method for the synthesis of quinoxaline derivatives with two benzimidazole fragments have been developed on the basis of the ring contraction of 3-(benzimidazo-2-yl)quinoxalin-2(1H)-one with 1,2-diaminobenzene and its various types of substituted and condensed derivatives. Owing to the inter- and intramolecular processes, involving self association, proton exchange, conformational, and/or tautomeric exchanges between several forms for most of the bis-benzimidazolylquinoxalines signals of bridged and neighboring carbon atoms and the hydrogen atoms of the neighboring carbon atoms of benzimidazole fragments in the NMR spectra are broadened. The conjugation between the benzimidazole fragments and the quinoxaline core of the molecules is increased from the quinoxaline derivative (10c) to its thiadiazol[f]- (17) and pyrrolo[a]-(19) annulated derivatives, resulting in a greater planarity of the molecule as a whole. [Copyright &y& Elsevier]

Abstract: An efficient and versatile one-step method for the synthesis of thiazolo[3,4-a]quinoxalines and related new heterocyclic systems have been developed on the basis of a new strategy for the construction of the pyrazine ring system. The key step of the process involves the cascade annulation of the iminothiazolopyrazine system to benzene in the reaction of 4-hydroxy-3,5-diaryl-2-phenyliminothiazolidines with 1,2-diaminobenzenes. The use of selenium analogues instead of thiazolidine derivatives in this reaction, leads to selenazolo[3,4-a]quinoxalines and the use of aza analogues instead of 1,2-diaminobenzenes gives aza analogues of thiazolo[3,4-a]quinoxalines. [Copyright &y& Elsevier]

Abstract: A simple and highly efficient metal-free method for the synthesis of 2-(pyrazin-2-yl)benzimidazoles has been developed on the basis of the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2-ones with diaminomaleonitrile. [Copyright &y& Elsevier]

Abstract: 3-Aroylquinoxalin-2(1H)-ones were found to be hetero analogues of α-diketones for the efficient, one-pot, three component synthesis of 2,4,5-trisubstituted imidazoles and imidazo[1,5-a]quinoxalin-4(5H)-ones in boiling methanol. The key advantages of this process are high yields, ready availability and low cost of 3-aroylquinoxalin-2(1H)-ones and easy work-up and separation of the products by non-chromatographic methods. Furthermore, the presence of an ortho-iminoanilide fragment at position 4 of the imidazoles obtained has made it possible to produce 2-(imidazol-4-yl)benzimidazoles in almost quantitative yields. [Copyright &y& Elsevier]

Abstract: An efficient and one-step versatile method for the synthesis of benzimidazoles and 1H-imidazo[4,5-b]pyridines from quinoxalinones and their aza-analogues have been developed on the basis of the novel ring contractions of 3-aroyl-quinoxalinones and their aza-analogues with 1,2-arylenediamines. [ABSTRACT FROM AUTHOR]

Interaction of quinoxalin-2(1 H)-one-3-carbaldoximes with 1,2-benzenediamine derivatives in AcOH or n -BuOH at reflux in the presence of sulfuric acid as catalyst was found to give 3-(benzimidazol-2-yl)quinoxalin-2(1 H)-ones and 2-(benzimidazol-2-yl)quinoxalines in relatively good yields, which formed as a result of the Weidenhagen reaction and Mamedov rearrangement, respectively. The reaction in AcOH afforded 2-(benzimidazol-2-yl)quinoxalines in preference to the 3-(benzimidazol-2-yl)quinoxalin-2(1 H)-ones, while the reverse result was obtained in n -BuOH. The synthetic utility of this strategy was illustrated by the concise, one-pot synthesis of 3-(3 H -imidazo[4,5- b pyridin-2-yl)quinoxalin-2(1 H)-ones. Image 1 • Quinoxalin-2(1 H)-one-3-carbaldoximes was used for synthesizing benzimidazol-2-ylquinoxalin(on)es. • Quinoxalin-2(1 H)-one-3-carbaldoximes was used for synthesizing 3-(3 H -imidazo[4,5- b pyridin-2-yl)quinoxalin-2(1 H)-ones. • Weidenhagen reaction was used for synthesizing 3-(benzimidazol-2-yl)quinoxalin-1 H)-ones. • Mamedov rearrangement was used for synthesizing 2-(benzimidazol-2-yl)quinoxalines. [ABSTRACT FROM AUTHOR]

The reaction of 3-aroylquinoxalin-2(1 H )-ones with α-amino acids and their derivatives, amines with various alkyl groups, amino alcohols with alkylene groups of various length, N -(3-aminopropyl)morpholine and 1,6-diaminohexane in DMSO at 150 °C proceeds through the oxidative cyclocondensation and makes it possible to synthesize substituted imidazo[1,5- a ]quinoxalines. Depending on the compound with the aminomethylene fragment used the reaction allows to introduction of any given substituent into position 1. [ABSTRACT FROM AUTHOR]

The reaction of 3-ethoxycarbonylmethylene-3,4-dihydroquinoxalin-2(1 H )-one with the Vilsmeier reagent, the treatment of 3-(3,4-dihydroquinoxalin-2(1 H )-on-3-yl)-1,2-dihydro-1,5-benzodiazepin-2(1 H )-one hydrochloride with 10% sodium hydroxide and 3-benzimidazoylquinoxalin-2(1 H )-one with both 1,2-phenylenediamine dihydrochloride, and the reactions of 1,2-phenylenediamine have been reinvestigated and the structures of these reaction products have been revised. It has been shown that in all the three cases other regioisomers of products have been formed as distinct from the literature data. The mechanisms to explain the formation of the products are suggested. [ABSTRACT FROM AUTHOR]

A protocol has been developed for the efficient synthesis of structurally diverse 4-(benzimidazol-2-yl)quinolines via reactions of 3-(2-aminophenyl)quinoxalin-2(1H)-ones and ketones, including acetone, acetophenones, 1,3-pentanedione and ethyl acetoacetate. The selective formation of the very different quinoline derivatives depends on the structure of ketones. The key steps are proposed to involve the new acid-catalyzed rearrangement of the spiro-quinoxalinone derivatives formed in situ from the reaction of 3-(2-aminophenyl)quinoxalin-2(1H)-ones and ketones under the modified Friedländer reaction. This transformation would facilitate the synthesis by short reaction times, large-scale synthesis, simple and prompt isolation of the products, which are the main advantages of this procedure. [ABSTRACT FROM AUTHOR]

A novel and efficient procedure for the synthesis of structurally diverse benzimidazolylquinolines has been realized through a new acid-catalyzed quinoxalinone-benzimidazole rearrangement of the spiro-quinoxalinone derivatives formed in situ from the reaction of 3-(2-aminophenyl)quinoxalin-2(1H)-ones and different ketones. [ABSTRACT FROM AUTHOR]

Abstract: A highly efficient, one-step, versatile method for the synthesis of tetrahydroindoles has been developed on the basis of new ring formation in the reactions of 1-(1-pyrrolidino)cyclohexene with chloropyruvates. [Copyright &y& Elsevier]

Summary: Background: Identification of robust biomarkers of malignancy and methods to establish disease progression is a major goal in paediatric neuro-oncology. We investigated whether methylation of the TERT promoter can be a biomarker for malignancy and patient outcome in paediatric brain tumours. Methods: For the discovery cohort, we used samples obtained from patients with paediatric brain tumours and individuals with normal brain tissues stored at the German Cancer Research Center (Heidelberg, Germany). We used methylation arrays for genome-wide assessment of DNA. For the validation cohort, we used samples obtained from several tissues for which full clinical and follow-up data were available from two hospitals in Toronto (ON, Canada). We did methylation analysis using quantitative Sequenom and pyrosequencing of an identified region of the TERT promoter. We assessed TERT expression by real-time PCR. To establish whether the biomarker could be used to assess and predict progression, we analysed methylation in paired samples of tumours that transformed from low to high grade and from localised to metastatic, and in choroid plexus tumours of different grades. Finally, we investigated overall survival in patients with posterior fossa ependymomas in which the identified region was hypermethylated or not. All individuals responsible for assays were masked to the outcome of the patients. Findings: Analysis of 280 samples in the discovery cohort identified one CpG site (cg11625005) in which 78 (99%) of 79 samples from normal brain tissues and low-grade tumours were not hypermethylated, but 145 (72%) of 201 samples from malignant tumours were hypermethylated (>15% methylated; p<0·0001). Analysis of 68 samples in the validation cohort identified a subset of five CpG sites (henceforth, upstream of the transcription start site [UTSS]) that was hypermethylated in all malignant paediatric brain tumours that expressed TERT but not in normal tissues that did not express TERT (p<0·0001). UTSS had a positive predictive value of 1·00 (95% CI 0·95–1·00) and a negative predictive value of 0·95 (0·87–0·99). In two paired samples of paediatric gliomas, UTSS methylation increased during transformation from low to high grade; it also increased in two paired samples that progressed from localised to metastatic disease. Two of eight atypical papillomas that had high UTSS methylation progressed to carcinomas, while the other six assessed did not progress or require additional treatment. 5-year overall survival was 51% (95% CI 31–71) for 25 patients with hypermethylated UTSS posterior fossa ependymomas and 95% (86–100) for 20 with non-hypermethylated tumours (p=0·0008). 5-year progression-free survival was 86% (68–100) for the 25 patients with non-hypermethylated UTSS tumours and 30% (10–50) for those with hypermethylated tumours (p=0·0008). Interpretation: Hypermethylation of the UTSS region in the TERT promoter is associated with TERT expression in cancers. In paediatric brain tumours, UTSS hypermethylation is associated with tumour progression and poor prognosis. This region is easy to amplify, and the assay to establish hypermethylation can be done on most tissues in most clinical laboratories. Therefore the UTSS region is a potentially accessible biomarker for various cancers. Funding: The Canadian Institute of Health Research and the Terry Fox Foundation. [ABSTRACT FROM AUTHOR]

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare cancer predisposition syndrome, presenting in childhood, in which affected patients develop various malignancies such as hematological, gastrointestinal and central nervous system tumors. Although guidelines are being increasingly developed for surveillance and early detection of cancers in affected families, there are no clear recommendations regarding choice of therapy and very scarce information about tolerance to chemotherapy and radiation in these patients. We report the pedigree of a consanguineous family with four affected children. Although clinical and molecular tests confirm CMMRD, genetic testing revealed heterogeneous mutations. The index case developed severe toxicity from therapy for glioblastoma and T-cell leukemia and died from an infection while in complete remission. His sister developed a malignant brain tumor while undergoing surveillance for a low grade brain lesion and is still undergoing follow-up. This family illustrates the difficulties and opportunities with challenging diagnosis, surveillance and choice of therapy for children with CMMRD and the need for increased awareness and more information about this rare but important syndrome. [ABSTRACT FROM AUTHOR]