title: Synthesis and cytotoxic properties of 4,11-bis[(aminoethyl)amino]anthra[2,3-b]thiophene-5,10-diones, novel analogues of antitumor anthracene-9,10-diones.
abstract: We developed the synthesis of a series of thiophene-fused tetracyclic analogues of the antitumor drug ametantrone. The reactions included nucleophilic substitution of methoxy groups in 4,11-dimethoxyanthra[2,3-b]thiophene-5,10-diones with ethylenediamines, producing the derivatives of 4,11-diaminoanthra[2,3-b]thiophene-5,10-dione in good yields. Several compounds showed marked antiproliferative potency against doxorubicin-selected, P-glycoprotein-expressing tumor cells and p53(-/-) cells. The cytotoxicity of some novel compounds for P-glycoprotein-positive cells is highly dependent on N-substituent at the terminal amino group of ethylenediamine moiety. The cytotoxic potency of selected compounds correlated with their ability to attenuate the functions of topoisomerase I and telomerase, strongly suggesting that these enzymes are the major targets of antitumor activity of anthra[2,3-b]thiophene-5,10-dione derivatives.
authors.affiliation: Gause Institute of New Antibiotics, Moscow, Russian Federation. shchekotikhin@mail.ru
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Shchekotikhin
authors.forename: Valeria A
authors.initials: VA
authors.lastname: Glazunova
authors.forename: Lyubov G
authors.initials: LG
authors.lastname: Dezhenkova
authors.forename: Yuri N
authors.initials: YN
authors.lastname: Luzikov
authors.forename: Yuri B
authors.initials: YB
authors.lastname: Sinkevich
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Kovalenko
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Buyanov
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Fong-Chun
authors.initials: FC
authors.lastname: Huang
authors.forename: Jing-Jer
authors.initials: JJ
authors.lastname: Lin
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D008942:Mitoxantrone; D004264:DNA Topoisomerases, Type I; C020182:ametantrone