ABSTRACT
In this paper, we present a copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones from 2-(2-bromophenyl)-N-(2-cyanophenyl)acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]quinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones as topoisomerase-I inhibitors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Copper/chemistry , Nitriles/chemistry , Quinolones/chemical synthesis , Quinolones/pharmacology , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Animals , Catalysis , DNA Topoisomerases, Type I/chemistry , Drug Design , Drug Screening Assays, Antitumor , Female , Humans , Male , Mice , Mice, Nude , Models, Molecular , Molecular Docking Simulation , Quinolones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Topoisomerase I Inhibitors/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
Using five bioinformatics analysis software, we identified Golgi protein 73 (GP73) as a putative target of microRNA-27b (miR-27b), which is closely related to various biological processes or diseases such as bone metabolism disease, adipose cell and muscle cell development, pulmonary hypertension, cervical cancer, and breast cancer. However, the clinical significance of miR-27b in hepatocellular carcinoma (HCC) is still unclear. The differential expression of miR-27b in HCC and adjacent normal liver tissues was measured by quantitative reverse transcription PCR. Our results showed that the expression of miR-27b in tumor tissues is lower than that in adjacent nontumor tissues. The expression of miR-27b was significantly lower in HCC tissues with high expression of GP73, when compared with adjacent nontumor tissues. Moreover, down-regulated expression of miR-27b was closely correlated with serum GP73, tumor-node-metastasis stage, tumor size, and portal vein thrombosis. GP73 mRNA might be a target of miR-27b. The 5-year overall survival rate of the low miR-27b expression group was significantly lower than that of the high miR-27b expression group. Moreover, multivariate analysis of prognostic factors, with a Cox proportional hazards model, showed that low miR-27b expression was a significant and independent predictor of poor survival in HCC. Hence, the abnormal expression of miR-27b might be related to the occurrence and development of tumors. Similarly, a study in the Cancer Genome Atlas database demonstrated that the expression of miR-27b in 50 normal individuals was 1.6 times higher than that of 372 patients with liver cancer. The overall survival rate of the low GP73 expression group (275 liver cancer patients) was significantly longer than that of the high GP73 expression group (90 normal individuals). MiR-27b suppresses the expression of GP73 and is therefore a potential prognostic biomarker and therapy target in HCC.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/pathology , Gene Expression Regulation, Neoplastic , Liver Neoplasms/pathology , Membrane Proteins/metabolism , MicroRNAs/genetics , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Proliferation , Disease Progression , Female , Follow-Up Studies , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Male , Membrane Proteins/genetics , Middle Aged , Prognosis , Survival RateABSTRACT
<p><b>OBJECTIVE</b>To investigate the prevalence and possible influencing factors of depressive disorder in surgical inpatients.</p><p><b>METHODS</b>Two hundred and sixty-six surgical inpatients meeting the inclusion criteria were first screened with the self rating depression scale (SDS), and then the subjects screened positive and 20% of those screened negative were evaluated with Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) as a gold standard for diagnosis of depressive disorder. Possible influencing factors were also analyzed by experienced psychiatrists.</p><p><b>RESULTS</b>The standard score of SDS in the surgical inpatients were significantly higher than those in the Chinese norm, and the incidence of depressive disorder in the surgical inpatients was 37.2%. Unvaried analysis showed that depressive disorder were associated with gender, education, economic condition, variety of diseases, hospitalization duration, and treatment methods. Logistic regression analysis revealed that gender, economic condition, treatment methods and previous history were the main influencing factors.</p><p><b>CONCLUSIONS</b>The incidence of depressive disorder in the surgical inpatients is high, and it is mainly influenced by gender, economic condition, treatment methods and previous history.</p>
