Type I [4σ+4π] versus [4σ+4π-1] Cycloaddition To Access Medium-Sized Carbocycles and Discovery of a Liver X Receptor ß-Selective Ligand.

Transition-metal-catalyzed [4+4] cycloaddition leading to cyclooctanoids has centered on dimerization between 1,3-diene-type substrates. Herein, we describe a [4σ+4π-1] and [4σ+4π] cycloaddition strategy to access 7/8-membered fused carbocycles through rhodium-catalyzed coupling between the 4σ-donor (benzocyclobutenones) and pendant diene (4π) motifs. The two pathways can be controlled by adjusting the solvated CO concentration. A broad range (>40 examples) of 5-6-7 and 5-6-8 polyfused carbocycles was obtained in good yields (up to 90 %). DFT calculations, kinetic monitoring and 13C-labeling experiments were carried out, suggesting a plausible mechanism. Notably, one 5-6-7 tricycle was found to be a very rare, potent, and selective ligand for the liver X receptor ß (KD=0.64 µM), which is a potential therapeutic target for cholesterol-metabolism-related fatal diseases.

Total Synthesis of Galanthamine and Lycoramine Featuring an Early-Stage C-C and a Late-Stage Dehydrogenation via C-H Activation.

Herein, we report a novel strategy toward galanthamine and lycoramine. The concise synthesis was enabled by a Rh-catalyzed gram-scale C-C activation for the tetracyclic carbon framework and a regioselective Pd-catalyzed C-H activation for double-bond introduction. An aqueous-phase Beckmann rearrangement was performed for nitrogen atom insertion. Galanthamine and lycoramine were completed in 11 and 10 steps, respectively.

Potential role of microRNAs in the treatment and diagnosis of cervical cancer.

Invasive cervical cancer is a leading cause of cancer death in women worldwide. miRNA may have roles in the pathogenesis of cervical cancer based on the increases or decreases in several specific miRNAs found in patients with this disease. The clinical outcomes of cervical cancer vary significantly and are difficult to predict. One unique challenge in cervical cancer biomarker study is the lack of large amounts of tumor tissues because most cervix biopsies are relatively small. The miRNA can affect HPV DNA replication shed more light on our understanding of the HPV life cycle and the mechanistic underpinnings of HPV induced oncogenesis. Also, miRNA processing proteins may be involved during early cervical cancer development. The E6 and E7 oncoproteins of HPV could induce the overexpression of DNA methyltransferase enzymes, which can catalyze the aberrant methylation of protein-coding and miRNA genes. Methods for diagnosis of cervical cancer include analysis of changes in the levels of specific miRNAs in serum and determination of aberrant hypermethylation of miRNAs. miRNAs are related on drug resistance and may be useful in combination therapy for cervical cancer with other drugs.

Upregulation of microRNA-224 is associated with aggressive progression and poor prognosis in human cervical cancer.

OBJECTIVE: Accumulating evidence for differential expression of microRNA-224 (miR-224) in various types of human cancer suggests that it may be play a crucial role in tumor biology. The previous microarray detection also shown that miR-224 was one of miRNAs with significant upregulation in cervical cancer tissues relative to adjacent normal tissues. However, little is known about the function of miR-224 in human cervical cancer. The aim of this study was to investigate the clinical significance of miR-224 expression in cervical cancer. METHODS: MiR-224 expression in 126 pairs of fresh human cervical cancer and adjacent normal tissues was measured by real-time quantitative RT-PCR assay. RESULTS: miR-224 expression was significantly upregulated in cervical cancer tissues when compared with corresponding adjacent normal tissues (P<0.001). It was also significantly higher in the cancerous tissues of patients with advanced FIGO stage cervical cancer than those with early FIGO stage (P=0.02). In addition, miR-224 was expressed at significantly higher levels in lymph node metastasis-positive patients than in lymph node metastasis-negative patients (P=0.008). Moreover, we found that lesser differentiated tumors expressed higher miR-224 (P=0.03). Finally, there were sufficient evidence to confirm its value in the status of vascular invasion (P=0.01) and human papillomavirus (HPV) infection (P=0.02) in cervical cancer. More importantly, Kaplan-Meier analysis showed that cervical cancer patients with high miR-224 expression tend to have shorter overall survival. In multivariate analysis stratified for known prognostic variables, miR-224 was identified as an independent prognostic marker. CONCLUSION: Our data indicated that miR-224 upregulation was associated with aggressive progression and poor prognosis in cervical cancer. MiR-224 was identified for the first time as an independent marker for predicting the clinical outcome of cervical cancer patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2170449349527493.