title: Synthesis and antiproliferative activity of conformationally restricted 1,2,3-triazole analogues of combretastatins in the sea urchin embryo model and against human cancer cell lines.
abstract: A series of 1,5-diaryl- and 4,5-diaryl-1,2,3-triazole derivatives of combretastatin A4 were synthesized and evaluated as antimitotic microtubule destabilizing agents using the sea urchin embryo model. Structure-activity relationship studies identified compounds substituted with 3,4,5-trimethoxyphenyl and 3,4-methylenedioxy-5-methoxyphenyl ring A and 4-methoxyphenyl ring B as potent antiproliferative agents with high cytotoxicity against a panel of human cancer cell lines including multi-drug resistant cells. 4,5-Diaryl-1,2,3-triazoles (C-C geometry) were found to be considerably more active than the respective 1,5-diaryl-1,2,3-triazoles (N-C geometry). Compound 10ad' induced G2/M cell cycle arrest and apoptosis in human T-leukemia Jurkat cells via caspase 2/3/9 activation and downregulation of the antiapoptotic protein XIAP. A mitotic catastrophe has been evaluated as another possible cell death mode.
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: demchuk@ioc.ac.ru.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Demchuk
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: sametav@ioc.ac.ru.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Samet
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: info@chemblock.com.
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Chernysheva
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: ushkarov@inbox.ru.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Ushkarov
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: galina_stashina@chemical-block.com.
authors.forename: Galina A
authors.initials: GA
authors.lastname: Stashina
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 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, 47 Leninsky Prospect, 119991 Moscow, Russian Federation; Chemical Block Ltd, 3 Kyriacou Matsi, 3723 Limassol, Cyprus. Electronic address: mr@chemical-block.com.
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Raihstat
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: cbi@chemical-block.com.
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Firgang
authors.affiliation: R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl'kivska Street, 03022 Kyiv, Ukraine. Electronic address: a_philch@onconet.kiev.ua.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Philchenkov
authors.affiliation: R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl'kivska Street, 03022 Kyiv, Ukraine. Electronic address: butenko@onconet.kiev.ua.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Zavelevich
authors.affiliation: R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl'kivska Street, 03022 Kyiv, Ukraine. Electronic address: kuyavalm@ukr.net.
authors.forename: Ludmila M
authors.initials: LM
authors.lastname: Kuiava
authors.affiliation: R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl'kivska Street, 03022 Kyiv, Ukraine. Electronic address: chekhun@onconet.kiev.ua.
authors.forename: Vasyl F
authors.initials: VF
authors.lastname: Chekhun
authors.affiliation: Department of Biological and Medicinal Chemistry, Moscow Institute of Physics and Technology, Institutsky Per. 9, Dolgoprudny, Moscow Region, 141700, Russia. Electronic address: blokhin@yandex.ru.
authors.forename: Dmitry Yu
authors.initials: DY
authors.lastname: Blokhin
authors.affiliation: ChemDiv, 6605 Nancy Ridge Drive, San Diego, CA 92121, USA. Electronic address: akiselyov@chemdiv.com.
authors.forename: Alex S
authors.initials: AS
authors.lastname: Kiselyov
authors.affiliation: 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.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Semenova
authors.affiliation: 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: vs@zelinsky.ru.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Semenov
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D023421:Models, Animal; D008968:Molecular Conformation; D010641:Phenotype; D012617:Sea Urchins / Q000187:drug effects* / Q000196:embryology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D014230:Triazoles; C040105:combretastatin
keywords: 1,2,3-Triazole; AODAGYGNZDUVNE-UHFFFAOYSA-N; ASLUYQCBIKMJEU-UHFFFAOYSA-N; Apoptosis; B-cell lymphoma 2; BKSKBNPDOWPAIO-UHFFFAOYSA-N; BLZMTDZGGLTDRK-UHFFFAOYSA-N; Bcl-2; CA2; CA4; CA4 disodium phosphate; CA4P; Caspases; DGTARDXIKVVWRO-UHFFFAOYSA-N; DOZOVRQLBANESF-UHFFFAOYSA-N; FODBYKDYGDVMRL-UHFFFAOYSA-N; FXJWTEDHYUZWTB-UHFFFAOYSA-N; GMMZILPCMBXPAN-UHFFFAOYSA-N; GZOVKXTXKMUHLY-UHFFFAOYSA-N; HDKAKWQYWMYIBD-UHFFFAOYSA-N; HHGRWXNBXGCVQC-UHFFFAOYSA-N; IMOWNIZUMDTJSQ-UHFFFAOYSA-N; JHZMSGCUGQSNOA-UHFFFAOYSA-N; JNDJXILHVKVNJP-UHFFFAOYSA-N; KAADNOIRUAPIJA-UHFFFAOYSA-N; KSXSFROOOPRMBN-UHFFFAOYSA-N; LDAGHTYWGJDFRH-UHFFFAOYSA-N; MNDDRAXBOYBUGK-UHFFFAOYSA-N; Microtubule destabilizing agents; MoAb; OXFHSVYQNFVGTK-UHFFFAOYSA-N; PARP-1; PI; PLIMGILENGQOOC-UHFFFAOYSA-N; Plant polyalkoxybenzenes; QZZHJHZNLFRILP-UHFFFAOYSA-N; SAR; Sea urchin embryo; VFOXVLIPSYMQEK-UHFFFAOYSA-N; VYIKEPOZDAQBBG-UHFFFAOYSA-N; X-linked inhibitor of apoptosis; XAYFGZPYFSZKTA-UHFFFAOYSA-N; XIAP; YZUDFBGHMYEADF-UHFFFAOYSA-N; combretastatin A-2; combretastatin A-4; monoclonal antibody; poly(ADP-ribose) polymerase-1; propidium iodide; structure–activity relationship