title: 3-Amino-thieno[2,3-b]pyridines as microtubule-destabilising agents: Molecular modelling and biological evaluation in the sea urchin embryo and human cancer cells.
abstract: A series of 3-amino-thieno[2,3-b]pyridines was prepared and tested in a phenotypic sea urchin embryo assay to identify potent and specific molecules that affect tubulin dynamics. The most active compounds featured a tricyclic core ring system with a fused cycloheptyl or cyclohexyl substituent and unsubstituted or alkyl-substituted phenyl moiety tethered via a carboxamide. Low nano-molar potency was observed in the sea urchin embryos for the most active compounds (1-5) suggestive of a microtubule-destabilising effect. The molecular modelling studies indicated that the tubulin colchicine site is inhibited, which often leads to microtubule-destabilisation in line with the sea urchin embryo results. Finally, the identified hits displayed a robust growth inhibition (GI50of 50-250nM) of multidrug-resistant melanoma MDA-MB-435 and breast MDA-MB-468 human cancer cell lines. This work demonstrates that for the thieno[2,3-b]pyridines the most effective mechanism of action is microtubule-destabilisation initiated by binding to the colchicine pocket.
authors.affiliation: School of Chemical Sciences, University of Auckland, New Zealand.
authors.forename: Chatchakorn
authors.initials: C
authors.lastname: Eurtivong
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
authors.forename: Victor
authors.initials: V
authors.lastname: Semenov
authors.affiliation: N. K. Kol'tsov Institute of Developmental Biology RAS, 26 Vavilov Street, 119334 Moscow, Russian Federation; Chemical Block Ltd., 3 Kyriacou Matsi, 3723 Limassol, Cyprus.
authors.forename: Marina
authors.initials: M
authors.lastname: Semenova
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
authors.forename: Leonid
authors.initials: L
authors.lastname: Konyushkin
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
authors.forename: Olga
authors.initials: O
authors.lastname: Atamanenko
authors.affiliation: School of Chemical Sciences, University of Auckland, New Zealand. Electronic address: j.reynisson@auckland.ac.nz.
authors.forename: Jóhannes
authors.initials: J
authors.lastname: Reynisson
authors.affiliation: Department of Biological and Medicinal Chemistry, Moscow Institute of Physics and Technology, Institutsky Per. 9, Dolgoprudny, Moscow Region 141700, Russian Federation.
authors.forename: Alex
authors.initials: A
authors.lastname: Kiselyov
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012617:Sea Urchins / Q000187:drug effects* / Q000196:embryology; D013329:Structure-Activity Relationship
chemical_list: C000621778:3-amino-thieno(2,3-b)pyridine; D000970:Antineoplastic Agents; D011725:Pyridines
keywords: Anticancer; Microtubule-destabilisation; Molecular modelling; Sea urchin embryo assay; Thieno[2,3-b]pyridines