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

Eur J Med Chem. 2017 Jan 5:125:573-585. doi: 10.1016/j.ejmech.2016.09.075.

Victor V Semenov ¹, Boris V Lichitsky ², Andrey N Komogortsev ³, Arkady A Dudinov ⁴, Mikhail M Krayushkin ⁵, Leonid D Konyushkin ⁶, Olga P Atamanenko ⁷, Irina B Karmanova ⁸, Yuri A Strelenko ⁹, Boris Shor ¹⁰, Marina N Semenova ¹¹, Alex S Kiselyov ¹²

Affiliations

1 N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: vs@zelinsky.ru.
2 N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: blich2006@mail.ru.
3 N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: dna5@mail.ru.
4 N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: 1944ark@mail.ru.
5 N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: mkray@ioc.ac.ru.
6 N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: LeonidK@chemical-block.com.
7 N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: info@chemblock.com.
8 N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: vs@chemblock.ru.
9 N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: strel@ioc.ac.ru.
10 Immune Pharmaceuticals LLC, 430 East 29th Street, Suite 940, New York, NY, 10016, USA. Electronic address: boris.shor@immunepharma.com.
11 N. K. Kol'tsov Institute of Developmental Biology, RAS, Vavilov Street, 26, 119334, Moscow, Russian Federation; Chemical Block Ltd., 3 Kyriacou Matsi, 3723, Limassol, Cyprus. Electronic address: ms@chemical-block.com.
12 Life Sciences Center, Moscow Institute of Physics and Technology, Institutsky Per., 9, Dolgoprudny, Moscow Region, 141700, Russian Federation. Electronic address: nikizalp@aol.com.

PMID: 27718473 DOI: 10.1016/j.ejmech.2016.09.075

Abstract

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.

Keywords

Cytotoxicity; Dihydroisothiazolopyridinones; Isothiazoles; Microtubule destabilization; Sea urchin embryo.

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