title: Synthesis and anti-mitotic activity of 6,7-dihydro-4H-isothiazolo[4,5-b]pyridin-5-ones: In vivo and cell-based studies.
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 (IC50in 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.
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: vs@zelinsky.ru.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Semenov
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: blich2006@mail.ru.
authors.forename: Boris V
authors.initials: BV
authors.lastname: Lichitsky
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: dna5@mail.ru.
authors.forename: Andrey N
authors.initials: AN
authors.lastname: Komogortsev
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: 1944ark@mail.ru.
authors.forename: Arkady A
authors.initials: AA
authors.lastname: Dudinov
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: mkray@ioc.ac.ru.
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Krayushkin
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: LeonidK@chemical-block.com.
authors.forename: Leonid D
authors.initials: LD
authors.lastname: Konyushkin
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: info@chemblock.com.
authors.forename: Olga P
authors.initials: OP
authors.lastname: Atamanenko
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: vs@chemblock.ru.
authors.forename: Irina B
authors.initials: IB
authors.lastname: Karmanova
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation. Electronic address: strel@ioc.ac.ru.
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Strelenko
authors.affiliation: Immune Pharmaceuticals LLC, 430 East 29th Street, Suite 940, New York, NY, 10016, USA. Electronic address: boris.shor@immunepharma.com.
authors.forename: Boris
authors.initials: B
authors.lastname: Shor
authors.affiliation: 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.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Semenova
authors.affiliation: Life Sciences Center, Moscow Institute of Physics and Technology, Institutsky Per., 9, Dolgoprudny, Moscow Region, 141700, Russian Federation. Electronic address: nikizalp@aol.com.
authors.forename: Alex S
authors.initials: AS
authors.lastname: Kiselyov
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012617:Sea Urchins / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D050256:Antimitotic Agents; D011743:Pyrimidines; D013844:Thiazoles
keywords: Cytotoxicity; Dihydroisothiazolopyridinones; Isothiazoles; Microtubule destabilization; Sea urchin embryo