Computational modeling and target synthesis of monomethoxy-substituted o-diphenylisoxazoles with unexpectedly high antimitotic microtubule destabilizing activity

Computational modeling and target synthesis of monomethoxy-substituted o-diphenylisoxazoles with unexpectedly high antimitotic microtubule destabilizing activity Full article

Journal

Bioorganic & Medicinal Chemistry Letters
ISSN: 1464-3405 , E-ISSN: 0960-894X

Output data

Year: 2020, Volume: 30, Number: 23, Article number : 127608, Pages count : DOI: 10.1016/j.bmcl.2020.127608

Authors

Stroylov Victor S. ^1,2 , Svitanko Igor V. ^1,2 , Maksimenko Anna S. ¹ , Kislyi Victor P. ¹ , Semenova Marina N. ³ , Semenov Victor V. ¹

Affiliations

1	N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation
2	National Research University Higher School of Economics (HSE), 20 Myasnitskaya Street, 101000 Moscow, Russian Federation
3	N. K. Kol’tsov Institute of Developmental Biology RAS, 26 Vavilov Street, 119334 Moscow, Russian Federation

The ability of monomethoxy-substituted o-diphenylisoxazoles 2a-d to interact with the colchicine site of tubulin was predicted using computational modeling, docking studies, and calculation of binding affinity. The respective molecules were synthesized in high yields by three steps reaction using easily available benzaldehydes, acetophenones, and arylnitromethanes as starting material. The calculated antitubulin effect was confirmed in vivo in a sea urchin embryo model. Compounds 2a and 2c showed high antimitotic microtubule destabilizing activity compared to that of CA4. Isoxazole 2a also exhibited significant cytotoxicity against human cancer cells in NCI60 screen. For the first time, isoxazole-linked CA4 derivatives 2a and 2c with only one methoxy substituent were identified as potent antimitotic microtubule destabilizing agents. These molecules could be considered as promising structures for further optimization.

Stroylov V.S. , Svitanko I.V. , Maksimenko A.S. , Kislyi V.P. , Semenova M.N. , Semenov V.V.
Computational modeling and target synthesis of monomethoxy-substituted o-diphenylisoxazoles with unexpectedly high antimitotic microtubule destabilizing activity
Bioorganic & Medicinal Chemistry Letters. 2020. V.30. N23. 127608 . DOI: 10.1016/j.bmcl.2020.127608 WOS Scopus OpenAlex

Web of science:	WOS:000595004500001
Scopus:	2-s2.0-85092717736
OpenAlex:	W3092030348

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OpenAlex	14
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Web of science	14