TY - JOUR

T1 - Identification of diaryl 5-amino-1,2,4-oxadiazoles as tubulin inhibitors

T2 - The special case of 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole

AU - Gakh, Andrei A.

AU - Sosnov, Andrey V.

AU - Krasavin, Mikhail

AU - Nguyen, Tam Luong

AU - Hamel, Ernest

N1 - Funding Information: This letter is a contribution from the Discovery Chemistry Project funded in part by the U.S. Department of Energy in collaboration with NCI . Oak Ridge National Laboratory is managed and operated by UT-Battelle, LLC , under contract DE-AC05-00OR22725 for the U.S. Department of Energy. In addition, this work has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health , under contract N01-CO-12400 . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute . Copyright: Copyright 2014 Elsevier B.V., All rights reserved.

PY - 2013/3/1

Y1 - 2013/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84873740047&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2013.01.007

DO - 10.1016/j.bmcl.2013.01.007

M3 - Article

C2 - 23385208

VL - 23

SP - 1262

EP - 1268

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 5

ER -