title: Novel antitumor L-arabinose derivative of indolocarbazole with high affinity to DNA.
abstract: Novel indolocarbazole derivative 12-(alpha-L-arabinopyranosyl)indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7-dione (AIC) demonstrated high potency (at submicromolar concentrations) against the NCI panel of human tumor cell lines and transplanted tumors in vivo. In search of tentative targets for AIC, we found that the drug formed high affinity intercalative complexes with d(AT)(20), d(GC)(20) and calf thymus DNA (binding constants (1.6x10(6)) M(-1)< or =K(a)< or =(3.3x10(6)) M(-1)). The drug intercalated preferentially into GC pairs of the duplex. Importantly, the concentrations at which AIC formed the intercalative complexes with DNA (C< or =1 microM) were identical to the concentrations that triggered p53-dependent gene reporter transactivation, the replication block, the inhibition of topoisomerase I-mediated DNA relaxation and death of HCT116 human colon carcinoma cells. We conclude that the formation of high affinity intercalative complexes with DNA is an important factor for anticancer efficacy of AIC.
authors: Engelhardt Institute of Molecular Biology, 32 Vavilov Street, Moscow 119991 (Russian Federation).
authors: Dmitry N
authors: DN
authors: Kaluzhny
authors: Victor V
authors: VV
authors: Tatarskiy
authors: Lyubov G
authors: LG
authors: Dezhenkova
authors: Irina L
authors: IL
authors: Plikhtyak
authors: Tatyana D
authors: TD
authors: Miniker
authors: Anna K
authors: AK
authors: Shchyolkina
authors: Sergey A
authors: SA
authors: Strel'tsov
authors: Ghermes G
authors: GG
authors: Chilov
authors: Fedor N
authors: FN
authors: Novikov
authors: Irina Yu
authors: IY
authors: Kubasova
authors: Zoya S
authors: ZS
authors: Smirnova
authors: Stalina Ya
authors: SY
authors: Mel'nik
authors: Mikhail A
authors: MA
authors: Livshits
authors: Olga F
authors: OF
authors: Borisova
authors: Alexander A
authors: AA
authors: Shtil
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D001089:Arabinose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D013050:Spectrometry, Fluorescence; D023041:Xenograft Model Antitumor Assays
chemical_list: C545676:12-(arabinopyranosyl)indolo(2,3-alpha)pyrrolo(3,4-c)carbazole-5,7-dione; D000970:Antineoplastic Agents; D002227:Carbazoles; D007364:Intercalating Agents; D004247:DNA; C427203:calf thymus DNA; D001089:Arabinose