Regioselective synthesis and biological evaluation of N-substituted 2-aminoquinazolin-4-ones.

The reaction of methyl anthranilates with N-arylcyanamides in the presence of p-TsOH in t-BuOH under reflux afforded predominantly 3-arylquinazolin-4-ones. In contrast, the reaction of the same reactants with TMSCl in t-BuOH at 60 °C followed by the Dimroth rearrangement in aqueous ethanolic sodium hydroxide gave exclusively the regioisomers, 2-(N-arylamino)quinazolin-4-ones. The regioselective synthesis of N-aryl-substituted 2-aminoquinazolin-4-ones can be further applied to the synthesis of benzimidazo[2,1-b]quinazolin-12-ones.

CuI-Catalyzed intramolecular aminocyanation of terminal alkynes in N-(2-ethynylphenyl)-N-sulfonylcyanamides via Cu-vinylidene intermediates.

CuI-Catalyzed intramolecular aminocyanation of terminal alkynes in N-(2-ethynylphenyl)-N-sulfonylcyanamides was initiated by the formation of Cu-acetylide to trigger N-CN bond cleavage of the N-sulfonylcyanamide moiety followed by CN migration to form a ß-cyano Cu-vinylidene intermediate. Subsequently, the indole ring closure furnished the corresponding 1-sulfonyl-3-cyanoindoles.

Promoter mutation of tumor suppressor microRNA-7 is associated with poor prognosis of lung cancer.

The significance of promoter mutations of microRNAs (miRNAs) in lung cancer is poorly understood. Recent evidence demonstrated that miRNA-7 (miR-7), a unique member of the miRNA family, exhibited decreased expression and has emerged as an important regulator in lung tumorigenesis. However, the mechanism underlying the downregulation of miR-7 in lung cancer remains largely unknown. In this study, we investigated the sites of mutation of the miR-7 promoter in lung cancer tissues using DNA sequencing. We identified a G→C change at the -617 site (25/39, 64.1%) and an A→G change at the -604 site (20/39, 51.3%) in the miR-7 promoter region in lung cancer tissues. Moreover, the expression of miR-7 in cancer tissue with promoter site mutations was lower compared with that in cancer tissue without mutations (P<0.05). Furthermore, we demonstrated that mutations at these sites may decrease the activity of the miR-7 promoter and alter the expression of miR-7. Notably, mutations at these sites of the miR-7 promoter were found to be closely associated with poor prognosis of lung cancer patients (P=0.037). These data may provide novel insight on the altered expression of specific miRNA molecules in lung cancer and ultimately prove to be helpful in the development of prognostic and therapeutic strategies against lung cancer.

[Over-expressed microRNA-7 inhibits the growth of human lung cancer cells via suppressing CGGBP1 expression].

OBJECTIVE: To investigate the effect of microRNA-7 (miR-7) over-expression on the growth of human lung cancer cells in vivo and in vitro and explore its possible mechanism. METHODS: The eukaryotic expression vector of pcDNA3.1 encoding miR-7 (p-miR-7) was transiently transfected into human lung cancer 95D cells in vitro. The proliferation of cells was detected by MTT assay and colony formation assay. Moreover, the expressions of nuclear antigen Ki-67 and CGG binding protein 1 (CGGBP1) were detected by immunofluorescence assay. Human lung cancer model in nude mice was established. Next, p-miR-7 vector was directly injected into local tumor tissue. Then, tumor size was measured and the survival time of mice was observed. The expression level of miR-7 in the tumor tissue was determined by real-time PCR. Finally, the expressions of Ki-67 and CGGBP1 were detected by immunohistochemistry. RESULTS: Over-expression of miR-7 could significantly inhibit the growth of 95D cells in vitro (P<0.05), accompanied by the remarkably reduced expressions of Ki-67 and CGGBP1 (P<0.05). Moreover, compared with those in control group, the expression level of miR-7 increased significantly in p-miR-7 injected group (P<0.05). Meanwhile, the growth of tumors in injected group was slower than in the control group. Consistently, the survival time of mice was dramatically prolonged in p-miR-7 injected group (P<0.05). The expression levels of Ki-67 and CGGBP1 also remarkably decreased in tumor tissue (P<0.05). CONCLUSION: Over-expression of miR-7 could significantly inhibit the growth of human lung cancer cells in vivo and in vitro, which might be related to the down-regulated expression of tumor growth-associated protein CGGBP1.

Practical synthesis of N-substituted cyanamides via Tiemann rearrangement of amidoximes.

A facile and general synthesis of various N-substituted cyanamides was accomplished by the Tiemann rearrangement of amidoximes with benzenesulfonyl chlorides (TsCl or o-NsCl) and DIPEA.

Antisense oligonucleotide treatment enhances the recovery of acute lung injury through IL-10-secreting M2-like macrophage-induced expansion of CD4+ regulatory T cells.

MicroRNAs (miRNAs) have been shown as an important regulator in the pathologies of acute lung injury (ALI). However, the potential effect of miRNA-based therapeutic studies in ALI remains poorly understood. We assessed the effect of antisense oligonucleotides (ASOs) against miR-155 on the development of ALI using a murine ALI model. We found that miR-155 ASO treatment could enhance the recovery of ALI as evidenced by accelerated body weight back, reduced level of bronchoalveolar lavage (BAL) protein and proinflammatory cytokines, and reduced number of BAL cells. Adoptive cell transfer assay in RAG1(-/-) mice showed that CD4(+)CD25(+) regulatory T cells (Tregs) mediated the enhanced recovery of ALI. Mechanistic evidence showed that enhanced expansion of Tregs in vivo, dominantly induced by IL-10-secreting M2-like macrophages, was critical for their elevated proportion in miR-155 ASO-treated ALI mice. Finally, we report that C/EBPß, a target molecule of miR-155, was upregulated and associated with IL-10 secretion and M2-like phenotype of macrophages. These data provided a previously unknown mechanism for miRNA-based therapy against ALI, which could ultimately aid the understanding of recovery of ALI and the development of new therapeutic strategies against clinical inflammatory lung disease.