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.
Keywords
Antitumor activity
Circumvention of multidrug resistance
DNA ligands
Naphtho[2
3-f]indole-5
10-diones
Topoisomerase 1/2 inhibitors
MeSH 主题词
Animals
Antineoplastic Agents/chemical synthesis,chemistry,pharmacology
Cattle
Cell Proliferation/drug effects
Cell Survival/drug effects
DNA/drug effects
DNA Cleavage/drug effects
DNA Topoisomerases, Type I/metabolism
DNA Topoisomerases, Type II/metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Humans
Indoles/chemical synthesis,chemistry,pharmacology
K562 Cells
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Molecular Structure
Naphthols/chemical synthesis,chemistry,pharmacology
Structure-Activity Relationship
Topoisomerase Inhibitors/chemical synthesis,chemistry,pharmacology
Tumor Cells, Cultured
化学物质
Antineoplastic Agents
Indoles
Naphthols
Topoisomerase Inhibitors
DNA
calf thymus DNA
DNA Topoisomerases, Type I
DNA Topoisomerases, Type II
作者与单位
共 14 位作者，点击展开单位 / ORCID
Shchekotikhin Andrey E
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:
[email protected].
Glazunova Valeria A
Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia; Moscow Engineering and Physics Institute, 31 Kashirskoye Shosse, Moscow 115409, Russia.
Dezhenkova Lyubov G
Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
Luzikov Yuri N
Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
Buyanov Vladimir N
Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia.
Treshalina Helena M
Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia.
Lesnaya Nina A
Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia.
Romanenko Vladimir I
Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia.
Kaluzhny Dmitry N
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
Balzarini Jan
Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
Agama Keli
Developmental Therapeutics Branch, National Cancer Institute, NIH, 37 Convent Drive, 37-5068, Bethesda, MD 20892, USA.
Pommier Yves
Developmental Therapeutics Branch, National Cancer Institute, NIH, 37 Convent Drive, 37-5068, Bethesda, MD 20892, USA.
Shtil Alexander A
Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia; Moscow Engineering and Physics Institute, 31 Kashirskoye Shosse, Moscow 115409, Russia.
Preobrazhenskaya Maria N
Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
