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Novel Antitumor L ‐Arabinose Derivative of Indolocarbazole with High Affinity to DNA
Author(s) -
Kaluzhny Dmitry N.,
Tatarskiy Victor V.,
Dezhenkova Lyubov G.,
Plikhtyak Irina L.,
Miniker Tatyana D.,
Shchyolkina Anna K.,
Strel'tsov Sergey A.,
Chilov Ghermes G.,
Novikov Fedor N.,
Kubasova Irina Yu.,
Smirnova Zoya S.,
Mel'nik Stalina Ya.,
Livshits Mikhail A.,
Borisova Olga F.,
Shtil Alexander A.
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900227
Subject(s) - transactivation , topoisomerase , dna , in vivo , chemistry , stereochemistry , derivative (finance) , biology , microbiology and biotechnology , gene , biochemistry , gene expression , genetics , financial economics , economics
Novel indolocarbazole derivative 12‐( α ‐ L ‐arabinopyranosyl)indolo[2,3‐ α ]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 (1.6×10 6 ) M −1 ≤ K a ≤(3.3×10 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 ≤1 μ M ) 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.