Identification of diaryl 5-amino-1,2,4-oxadiazoles as tubulin inhibitors: The special case of 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole |
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| Authors: | Andrei A Gakh Andrey V Sosnov Mikhail Krasavin Tam Luong Nguyen Ernest Hamel |
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| Institution: | 1. Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA;2. The University of Virginia, Charlottesville, VA 22908, USA;3. Discovery Chemistry Project, Bethesda, MD 20824, USA;4. ORCHIMED, Institute of Physiologically Active Compounds, Chernogolovka 142432, Russia;5. Griffith University, Nathan Qld 4111, Australia;6. Target Structure-Based Drug Discovery Group, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA;7. Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA |
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| Abstract: | The combination of experimental (inhibition of colchicine binding) and computational (COMPARE, docking studies) data unequivocally identified diaryl 5-amino-1,2,4-oxadiazoles as potent tubulin inhibitors. Good correlation was observed between tubulin binding and cytostatic properties for all tested compounds with the notable exception of the lead candidate, 3-(3-methoxyphenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole (DCP 10500078). This compound was found to be substantially more active in our in vitro experiments than the monofluorinated title compound, 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole (DCP 10500067/NSC 757486), which in turn demonstrated slightly better tubulin binding activity. Comparative SAR analysis of 25 diaryl 5-amino-1,2,4-oxadiazoles with other known tubulin inhibitors, such as combretastatin A-4 (CA-4) and colchicine, provides further insight into the specifics of their binding as well as a plausible mechanism of action. |
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