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Eur J Med Chem. 2014 Feb 12;73:112-25. doi: 10.1016/j.ejmech.2013.12.006. Epub 2013 Dec 16.

3-(5-)-Amino-o-diarylisoxazoles: regioselective synthesis and antitubulin activity.

Author information

1
N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: tsyg@ioc.ac.ru.
2
A. N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilov Street, 119991 Moscow, Russian Federation. Electronic address: vkh@xray.ineos.ac.ru.
3
N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: LeonidK@chemical-block.com.
4
N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation; Chemical Block Ltd., 3 Kyriacou Matsi, 3723 Limassol, Cyprus. Electronic address: mr@chemical-block.com.
5
N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: cbi@chemical-block.com.
6
N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: rs@chemical-block.com.
7
Department of Biological and Medicinal Chemistry, Moscow Institute of Physics and Technology, Institutsky Per. 9, Dolgoprudny, 141700 Moscow Region, Russian Federation. Electronic address: akiselyov@chemdiv.com.
8
Chemical Block Ltd., 3 Kyriacou Matsi, 3723 Limassol, Cyprus; N. K. Kol'tsov Institute of Developmental Biology RAS, 26 Vavilov Street, 119334 Moscow, Russian Federation. Electronic address: ms@chemical-block.com.
9
N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: vs@zelinsky.ru.

Abstract

A regioselective synthesis of both 5-amino- and 3-aminodiarylisoxazoles substituted with polyalkoxyaryl pharmacophores has been validated. Starting materials for the synthetic scheme were easily available from plant extracts. The targeted molecules were further tested in the phenotypic sea urchin embryo assay to identify compounds with antimitotic microtubule destabilizing activity. Structure-activity relationship studies suggested that the structural features essential for potent antiproliferative activity include: 1) 5-aminoisoxazole bridge linking biaryl substituents (rings A and B); 2) unsubstituted 5-amino group; 3) 3,4,5-methoxy substituted benzene and 4-methoxy benzene pharmacophores as rings A and B, respectively. The most potent compounds also showed strong in vitro cytotoxicity in NCI60 anticancer drug screen against a panel of 60 human cancer cell lines, including multi-drug resistant cells.

KEYWORDS:

Combretastatin; Cytotoxicity; Diarylaminoisoxazoles; Microtubule destabilizing agents; Plant polyalkoxybenzenes; Sea urchin embryo

PMID:
24388833
DOI:
10.1016/j.ejmech.2013.12.006
[Indexed for MEDLINE]
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