Gülçin Tuğcu1, Filiz Esra Önen Bayram2, Hande Sipahi1. 1. Yeditepe University Faculty of Pharmacy, Department of Toxicology, İstanbul, Turkey. 2. Yeditepe University Faculty of Pharmacy, Department of Pharmaceutical Chemistry, İstanbul, Turkey.
Abstract
OBJECTIVES: 4-(2-fluorophenoxy) quinoline derivatives constitute one of the chemical classes of hepatocyte growth factor receptor (c-MET) inhibitors, a promising treatment against various human tumors. There are three aims of the present study: (1) To develop a robust and validated quantitative structure-activity relationship model to predict the c-Met kinase inhibition; (2) to examine the toxicity profiles of these compounds; (3) to design new quinoline derivatives and apply the developed model on these compounds to observe its pertinence. MATERIALS AND METHODS: A multiple linear regression method was used to develop the model with calculated descriptors. State-of-the-art internal and external validation parameters were calculated. The in silico toxicity profiles including structural alerts and the lowest observed adverse effect level (LOAEL) values were evaluated using online tools. New derivatives were designed and tested on the developed model. RESULTS: A series of 4-(2-fluorophenoxy) quinoline derivatives was linearly modeled and vigorously validated to predict the molecules' c-MET kinase inhibition potential. Statistical metrics of the developed model showed that it was robust and able to make successful predictions for this chemical class. The mass, electronegativity, partial charges, and the structure of the molecules had an effect on the activity. Moreover, the toxicity profiles of the studied compounds were found to be adequate. CONCLUSION: Five of the synthesized compounds were observed to be auspicious for the toxicity/activity ratio. The developed model is useful in the virtual screening and in the design of new anti-tumor compounds.
OBJECTIVES: 4-(2-fluorophenoxy) quinoline derivatives constitute one of the chemical classes of hepatocyte growth factor receptor (c-MET) inhibitors, a promising treatment against various human tumors. There are three aims of the present study: (1) To develop a robust and validated quantitative structure-activity relationship model to predict the c-Met kinase inhibition; (2) to examine the toxicity profiles of these compounds; (3) to design new quinoline derivatives and apply the developed model on these compounds to observe its pertinence. MATERIALS AND METHODS: A multiple linear regression method was used to develop the model with calculated descriptors. State-of-the-art internal and external validation parameters were calculated. The in silico toxicity profiles including structural alerts and the lowest observed adverse effect level (LOAEL) values were evaluated using online tools. New derivatives were designed and tested on the developed model. RESULTS: A series of 4-(2-fluorophenoxy) quinoline derivatives was linearly modeled and vigorously validated to predict the molecules' c-MET kinase inhibition potential. Statistical metrics of the developed model showed that it was robust and able to make successful predictions for this chemical class. The mass, electronegativity, partial charges, and the structure of the molecules had an effect on the activity. Moreover, the toxicity profiles of the studied compounds were found to be adequate. CONCLUSION: Five of the synthesized compounds were observed to be auspicious for the toxicity/activity ratio. The developed model is useful in the virtual screening and in the design of new anti-tumor compounds.
Authors: Alan S Bass; Mark E Cartwright; Craig Mahon; Richard Morrison; Ronald Snyder; Paul McNamara; Prudence Bradley; Ying-Ying Zhou; John Hunter Journal: J Pharmacol Toxicol Methods Date: 2009-05-05 Impact factor: 1.950
Authors: Martijn P Lolkema; Hilde H Bohets; Hendrik-Tobias Arkenau; Ann Lampo; Erio Barale; Maja J A de Jonge; Leni van Doorn; Peter Hellemans; Johann S de Bono; Ferry A L M Eskens Journal: Clin Cancer Res Date: 2015-03-05 Impact factor: 12.531