title: Development of a novel class of tubulin inhibitor from desmosdumotin B with a hydroxylated bicyclic B-ring.
abstract: A series of newly synthesized hydroxylated analogues of triethyldesmosdumotin B (TEDB) with a bicyclic B-ring exhibited a significantly different mode of action for affecting microtubule dynamics and spindle formation but had the same antiproliferative activity spectrum, including activity against multidrug-resistant tumors. These analogues efficiently induced cell cycle arrest at prometaphase and caused formation of immature multipolar spindles. 6'-Hydroxyl TEDB-TB (8) disrupted bipolar spindle formation but had a negligible effect on interphase microtubules. On the basis of the predicted binding modes of the new compounds with tubulin dimer, compound 4 forms three hydrogen bonds (H-bonds) only with α-tubulin at the colchicine site; in contrast, 8 forms H-bonds with both α- and β-tubulin. We predict that, when a compound/ligand, such as 8, forms H-bonds to both α- and β-tubulins, spindle formation is disrupted more than the dynamics of interphase microtubules. This result may reflect the well-known greater dynamicity of spindle microtubules as compared with interphase microtubules.
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University , Kanazawa, 920-1192, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.forename: Akifumi
authors.initials: A
authors.lastname: Oda
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Emika
authors.initials: E
authors.lastname: Ohkoshi
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Masuo
authors.initials: M
authors.lastname: Goto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D055808:Drug Discovery; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D047309:Flavones / Q000737:chemistry* / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D006900:Hydroxylation; D008870:Microtubules / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C552711:6,6,8-triethyldesmosdumotin B; D000970:Antineoplastic Agents; D047309:Flavones; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine