Synthesis and anti-mitotic activity of 6,7-dihydro-4H-isothiazolo[4,5-b]pyridin-5-ones: In vivo and cell-based studies

Synthesis and anti-mitotic activity of 6,7-dihydro-4H-isothiazolo[4,5-b]pyridin-5-ones: In vivo and cell-based studies Full article

Journal

European Journal of Medicinal Chemistry
ISSN: 1768-3254 , E-ISSN: 0223-5234

Output data

Year: 2017, Volume: 125, Pages: 573-585 Pages count : 13 DOI: 10.1016/j.ejmech.2016.09.075

Authors

Semenov Victor V. ¹ , Lichitsky Boris V. ¹ , Komogortsev Andrey N. ¹ , Dudinov Arkady A. ¹ , Krayushkin Mikhail M. ¹ , Konyushkin Leonid D. ¹ , Atamanenko Olga P. ¹ , Karmanova Irina B. ¹ , Strelenko Yuri A. ¹ , Shor Boris ² , Semenova Marina N. ^3,4 , Kiselyov Alex S. ⁵

Affiliations

1	N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation
2	Immune Pharmaceuticals LLC, 430 East 29th Street, Suite 940, New York, NY, 10016, USA
3	Chemical Block Ltd., 3 Kyriacou Matsi, 3723, Limassol, Cyprus
4	N. K. Kol'tsov Institute of Developmental Biology, RAS, Vavilov Street, 26, 119334, Moscow, Russian Federation
5	Life Sciences Center, Moscow Institute of Physics and Technology, Institutsky Per., 9, Dolgoprudny, Moscow Region, 141700, Russian Federation

A series of 3,7-diaryl-6,7-dihydroisothiazolo [4,5-b]pyridin-5(4H)-ones 8 and 9 was synthesized by multicomponent condensation of 3-aryl-5-isothiazolecarboxylic acid esters 4a–f with aromatic (or thienyl) aldehydes 7 and Meldrum's acid in an acidic medium. The targeted compounds were evaluated for their antimitotic microtubule destabilizing activity using in vivo phenotypic sea urchin embryo model and in vitro human cancer cell-based assays. Selected dihydroisothiazolopyridinones altered sea urchin egg cleavage in 2–10 nM concentrations together with significant cytotoxicity against cancer cells including chemoresistant cell lines (IC50 in submicromolar – low nanomolar concentration range). Both approaches confirmed antimitotic microtubule destabilizing mechanism of action of the izothiazole derivatives. Structure-activity relationship study determined the importance of p-methoxybenzene A-ring for the antiproliferative effect. The most potent compound 9b containing p-methoxybenzene A-ring and thiophene B-ring caused mitotic arrest and disintegration of cell microtubules.

Semenov V.V. , Lichitsky B.V. , Komogortsev A.N. , Dudinov A.A. , Krayushkin M.M. , Konyushkin L.D. , Atamanenko O.P. , Karmanova I.B. , Strelenko Y.A. , Shor B. , Semenova M.N. , Kiselyov A.S.
Synthesis and anti-mitotic activity of 6,7-dihydro-4H-isothiazolo[4,5-b]pyridin-5-ones: In vivo and cell-based studies
European Journal of Medicinal Chemistry. 2017. V.125. P.573-585. DOI: 10.1016/j.ejmech.2016.09.075 WOS Scopus OpenAlex

Web of science:	WOS:000390496600045
Scopus:	2-s2.0-84989947718
OpenAlex:	W2521802771

DB	Citing
OpenAlex	20
Scopus	18
Web of science	16