ABSTRACT
A series of novel metronidazole aryloxy, carboxy and azole derivatives has been synthesized and their cytotoxic activities on three cancer cell lines were evaluated by MTT assay. Compounds 4m, 4l and 4d showed the most potent cytotoxic activity (IC50sâ¯less thanâ¯100⯵g/mL). Apoptosis was also detected for these compounds by flow cytometry. Docking studies were performed in order to propose the probable target protein. In the next step, molecular dynamics simulation was carried out on the proposed target protein, focal adhesion kinase (FAK, PDB code: 2ETM), bound to compound 4m. As, 4m showed a potent cytotoxic activity and an acceptable apoptotic effect, it can be a potential anticancer candidate that may work through inhibition of FAK.
Subject(s)
Antineoplastic Agents/pharmacology , Metronidazole/analogs & derivatives , Metronidazole/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Catalytic Domain , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Focal Adhesion Kinase 1/antagonists & inhibitors , Focal Adhesion Kinase 1/chemistry , Focal Adhesion Kinase 1/metabolism , Humans , Hydrogen Bonding , Metronidazole/chemical synthesis , Metronidazole/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Quantitative Structure-Activity RelationshipABSTRACT
Background: Red blood cell distribution width (RDW) is a quantitative measure of variability in the size of circulating erythrocytes. It has been recently identified as a prognostic marker in several diseases including acute pancreatitis (AP). In this systematic review the prognostic value of RDW in predicting mortality of AP patients will be assessed. Methods: PubMed, Scopus, EMBASE, and ISI databases were searched until September 2016 using the following search strategy: (pancreatitis OR pancreatitides) AND (RDW OR "red cell distribution width" OR "red blood cell distribution width" OR anisocytosis). Four authors independently reviewed the retrieved articles. Studies were included if they had evaluated the association between RDW value and mortality of acute pancreatitis patients. Case reports, comments, letters to the editor, reviews, study protocols, and experimental studies were not included. Data abstraction and quality assessment for the included studies was independently performed by two authors. Quality of studies was assessed using Oxford Center for Evidence-Based Medicine checklist for prognostic studies. Data were synthesized qualitatively, and a meta-analysis was performed on the diagnostic performance of RDW to predict mortality in AP patients. Results: Seven studies (976 patients) were included in the systematic review. Six studies reported a statistically significant association between RDW value and mortality. Meta-analysis was performed on four studies (487 patients) using a bivariate model and a summary receiver operating characteristic (sROC) curve was plotted with an area under the curve (AUC) of 0.757. The pooled diagnostic odds ratio (DOR), sensitivity and specificity was 19.51 (95% CI: 5.26-72.30), 67% (95% CI: 51%-80%) and 90% (95% CI: 73%-96%), respectively. Conclusion: RDW is an easy to use and an inexpensive marker with a moderate prognostic value to predict death in AP patients. Clinicians should be more alert when a patient with AP has an increased RDW. Investigation of possible combinations of other prognostic markers with RDW is recommended.
