ABSTRACT
A high-throughput screen for Ras-mitogen-activated protein kinase (MAPK) signaling inhibitors identified two series (class 1 and 2) of substituted 4-anilino-3-quinolinecarbonitriles as potent (IC(50)s <10 nmol/L) mitogen-activated protein/extracellular signal-regulated kinase 1 (MEK1) kinase inhibitors. These compounds had cyanoquinoline cores, but differed in their respective aniline groups [1a, 1b: 4-phenoxyphenylaniline; 2a, 2b: 3-chloro-4-(1-methylimidazol-2-sulfanyl)aniline]. These compounds were competitive inhibitors of ATP binding by MEK1 kinase, and they had minimal or no effect on Raf, epidermal growth factor receptor (EGFR), Akt, cyclin-dependent kinase 4 (CDK4), or MK2 kinases at concentrations >100-fold higher than those that inhibited MEK1 kinase. Both class 1 and 2 compounds inhibited in vitro growth of human tumor cell lines. A class 2 compound (2b) was the most potent inhibitor of human tumor cell growth in vitro, and this effect was linked to distinct suppression of MAPK phosphorylation in cells. Compound 2b did not affect phosphorylation status of other kinases, such as EGFR, Akt, and stress-activated protein (SAP)/c-jun-NH kinase (Jnk); nor did it affect overall tyrosine phosphorylation level in cells. However, compound 2b did inhibit MEK1 phosphorylation in cells. Inhibition of MEK1 phosphorylation by 2b was not due to a major effect on Raf kinase activity, because enzyme assays showed minimal Raf kinase inhibition. We believe compound 2b inhibits kinase activity upstream of Raf, and thereby affects MEK1 phosphorylation in cells. Even with the dual effect of 2b on MEK and MAPK phosphorylation, this compound was well tolerated and significantly inhibited growth of the human colon tumor cell line LoVo (at 50 and 100 mg/kg BID, i.p.) in a nude mouse xenograft model.
Subject(s)
Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , MAP Kinase Kinase 1/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Aniline Compounds/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/classification , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/classification , Humans , Inhibitory Concentration 50 , Kinetics , MAP Kinase Kinase 1/metabolism , MAP Kinase Signaling System/drug effects , Mice , Mice, Nude , Nitriles/chemistry , Nitriles/pharmacology , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Proto-Oncogene Proteins c-raf/metabolism , Quinolines/chemistry , Quinolines/pharmacology , Sensitivity and Specificity , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.
Subject(s)
Antineoplastic Agents/chemical synthesis , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Nitriles/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , MAP Kinase Kinase 1 , Mice , Neoplasms, Experimental/drug therapy , Nitriles/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Signal Transduction/drug effects , Structure-Activity Relationship , Transplantation, Heterologous , Treatment OutcomeABSTRACT
This study examines the distribution, understanding and objectives of nursing visits as well as the implementation and the experience with nursing visits in 87 hospitals in North Germany (Bremen, Lower Saxony, Hamburg, Schleswig-Holstein and Mecklenburg-Western Pomerania). The survey was conducted using a questionnaire. It was found that nursing visits are implemented in 31% of the departments. By means of the nursing visit the patients are involved in the nursing process. The objectives of nursing visits are patient orientation. and the improvement of the nursing quality. The nursing visit is criticised because of both the level of organisation and the time spent on nursing visits as well as the lack of training, maintaining confidentiality and questions of data protection. The study contributes to a better understanding of nursing visits and a clearer definition of the term. It is the first empirical study of this type that has been conducted in Germany.
Subject(s)
Community Health Nursing/statistics & numerical data , National Health Programs/statistics & numerical data , Quality Assurance, Health Care/statistics & numerical data , Germany , Home Care Services, Hospital-Based/statistics & numerical data , Humans , Nursing Administration ResearchABSTRACT
A series of 4-anilino-3-cyanobenzo[g]quinolines was prepared as potent kinase inhibitors. Compared with their bicyclic 4-anilino-3-cyanoquinoline analogues, the tricyclic 4-anilino-3-cyanobenzo[g]quinolines are less active against EGF-R kinase, equally active against MAPK kinase (MEK), and more active against Src kinase. For Src kinase inhibition, the best activity is obtained when both the 7- and 8-positions are substituted with alkoxy groups. Several of these kinase inhibitors show potent growth inhibitory activity in tumor cells.
