title: Synthesis and evaluation of new antitumor 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones.
abstract: A series of new 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones 6-13 bearing the cyclic diamine in the position 3 of the indole ring was synthesized. The majority of new compounds demonstrated a superior cytotoxicity than doxorubicin against a panel of mammalian tumor cells with determinants of altered drug response, that is, Pgp expression or p53 inactivation. For naphtho[2,3-f]indole-5,10-diones 6-9 bearing 3-aminopyrrolidine in the side chains, the ability to bind double-stranded DNA and inhibit topoisomerases 1 and 2 mediated relaxation of supercoiled DNA were demonstrated. Only one isomer, (R)-4,11-dihydroxy-3-((pyrrolidin-3-ylamino)methyl)-1H-naphtho[2,3-f]indole-5,10-dione (7) induced the formation of specific DNA cleavage products similar to the known topoisomerase 1 inhibitors camptothecin and indenoisoquinoline MJ-III-65, suggesting a role of the structure of the side chain of 3-aminomethylnaphtho[2,3-f]indole-5,10-diones in interaction with the target. Compound 7 demonstrated an antitumor activity in mice with P388 leukemia transplants whereas its enantiomer 6 was inactive. Thus, 3-aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione emerge as a new prospective chemotype for the search of antitumor agents.
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia. Electronic address: shchekotikhin@mail.ru.
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Shchekotikhin
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia; Moscow Engineering and Physics Institute, 31 Kashirskoye Shosse, Moscow 115409, Russia.
authors.forename: Valeria A
authors.initials: VA
authors.lastname: Glazunova
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Lyubov G
authors.initials: LG
authors.lastname: Dezhenkova
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Yuri N
authors.initials: YN
authors.lastname: Luzikov
authors.affiliation: Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Buyanov
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Treshalina
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia.
authors.forename: Nina A
authors.initials: NA
authors.lastname: Lesnaya
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Romanenko
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Kaluzhny
authors.affiliation: Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, 37 Convent Drive, 37-5068, Bethesda, MD 20892, USA.
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, 37 Convent Drive, 37-5068, Bethesda, MD 20892, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia; Moscow Engineering and Physics Institute, 31 Kashirskoye Shosse, Moscow 115409, Russia.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D053837:DNA Cleavage / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020014:K562 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009284:Naphthols; D059003:Topoisomerase Inhibitors; D004247:DNA; C427203:calf thymus DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II
keywords: Antitumor activity; Circumvention of multidrug resistance; DNA ligands; Naphtho[2,3-f]indole-5,10-diones; Topoisomerase 1/2 inhibitors