2. Academic Validation
  3. 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

  • Bioorg Med Chem Lett. 2020 Dec 1;30(23):127608. doi: 10.1016/j.bmcl.2020.127608.
Victor S Stroylov 1,  Igor V Svitanko 2,  Anna S Maksimenko 3,  Victor P Kislyi 4,  Marina N Semenova 5,  Victor V Semenov 6
Affiliations

Affiliations

  • 1 N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation; National Research University Higher School of Economics (HSE), 20 Myasnitskaya Street, 101000 Moscow, Russian Federation. Electronic address: [email protected].
  • 2 N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation; National Research University Higher School of Economics (HSE), 20 Myasnitskaya Street, 101000 Moscow, Russian Federation. Electronic address: [email protected].
  • 3 N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
  • 4 N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
  • 5 N. K. Kol'tsov Institute of Developmental Biology RAS, 26 Vavilov Street, 119334 Moscow, Russian Federation. Electronic address: [email protected].
  • 6 N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
PMID: 33038545 DOI: 10.1016/j.bmcl.2020.127608
Abstract

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.

Keywords

Computational modeling; Docking; Microtubule destabilization; Sea urchin embryo; o-Diarylisoxazoles.

Figures
Products