title: 3-(5-)-Amino-o-diarylisoxazoles: regioselective synthesis and antitubulin activity.
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.
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: tsyg@ioc.ac.ru.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Tsyganov
authors.affiliation: A. N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilov Street, 119991 Moscow, Russian Federation. Electronic address: vkh@xray.ineos.ac.ru.
authors.forename: Victor N
authors.initials: VN
authors.lastname: Khrustalev
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: N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: rs@chemical-block.com.
authors.forename: Roman V
authors.initials: RV
authors.lastname: Semenov
authors.affiliation: 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.
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. 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; D036703:Blastula / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D012617:Sea Urchins / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007555:Isoxazoles; D050257:Tubulin Modulators
keywords: Combretastatin; Cytotoxicity; Diarylaminoisoxazoles; Microtubule destabilizing agents; Plant polyalkoxybenzenes; Sea urchin embryo