title: 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.
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.
authors: Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA. gakhaa@yahoo.com
authors: Andrei A
authors: AA
authors: Gakh
authors: Andrey V
authors: AV
authors: Sosnov
authors: Mikhail
authors: M
authors: Krasavin
authors: Tam Luong
authors: TL
authors: Nguyen
authors: Ernest
authors: E
authors: Hamel
mesh_terms: D001665:Binding Sites; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D010069:Oxadiazoles; D050257:Tubulin Modulators
references: J Med Chem. 2010 May 27;53(10):4248-58
references: 20420439
references: Nat Rev Drug Discov. 2006 Oct;5(10):835-44
references: 17016424
references: J Med Chem. 2005 Oct 20;48(21):6523-43
references: 16220969
references: J Med Chem. 2012 May 10;55(9):4297-308
references: 22486652
references: Curr Med Chem. 2011;18(31):4722-37
references: 21919848
references: J Med Chem. 2005 Sep 22;48(19):6107-16
references: 16162011
references: Nat Rev Drug Discov. 2004 Apr;3(4):353-9
references: 15060530
references: Nature. 2004 Mar 11;428(6979):198-202
references: 15014504
references: J Med Chem. 2011 Jul 14;54(13):4678-93
references: 21557538
references: J Mol Graph Model. 2002 Jan;20(4):297-303
references: 11858638
references: Molecules. 2010 Feb 23;15(2):997-1006
references: 20335958
references: Drug Discov Today. 2004 Oct 1;9(19):826-7
references: 15381132
references: Nature. 1998 Jan 8;391(6663):199-203
references: 9428769
references: Nature. 2005 Oct 13;437(7061):942-3
references: 16222266
references: Drug Discov Today. 2007 Feb;12(3-4):156-60
references: 17275736
references: Pharm Res. 2012 Nov;29(11):2943-71
references: 22814904
references: J Med Chem. 2010 Oct 28;53(20):7414-27
references: 20919720
references: Arch Pharm (Weinheim). 2009 Jul;342(7):420-7
references: 19544302
references: Nat Biotechnol. 2005 Jun;23(6):639
references: 15940222
references: Int J Cancer. 2011 Jul 1;129(1):245-55
references: 21170960
references: Chem Cent J. 2010 Mar 09;4:4
references: 20214785
references: J Med Chem. 1993 Apr 30;36(9):1146-56
references: 8387598
references: J Med Chem. 2007 Feb 22;50(4):749-54
references: 17249649
references: Nature. 2012 Jun 10;486(7403):361-7
references: 22722194
references: J Med Chem. 2006 Jan 12;49(1):179-85
references: 16392802
references: Biochem Pharmacol. 1996 Jan 12;51(1):53-9
references: 8534268
references: Nat Rev Cancer. 2004 Apr;4(4):253-65
references: 15057285
references: Drug Discov Today. 2004 Aug 1;9(15):641-51
references: 15279847