title: Antitumor agents. 284. New desmosdumotin B analogues with bicyclic B-ring as cytotoxic and antitubulin agents.
abstract: We previously reported that the biological activity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI(50) values of 0.8-2.1 μM. In contrast, 1 analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistant cell line. We have now prepared and evaluated 1 analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI(50) values of 0.06-0.16 μM, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC(50) value of 2.0 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation.
authors.affiliation: Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States. Ken_Bastow@unc.edu
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Wu
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Lai
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.forename: Takashi
authors.initials: T
authors.lastname: Kozaka
authors.forename: Emika
authors.initials: E
authors.lastname: Ohkoshi
authors.forename: Masuo
authors.initials: M
authors.lastname: Goto
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003078:Colchicine / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C558511:2-(benzo(b)thiophen-3'-yl)-6,8,8-triethyldesmosdumotin B; D000970:Antineoplastic Agents; D002867:Chromones; D009281:Naphthalenes; D013876:Thiophenes; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine