Novel Antitumor L‐Arabinose Derivative of Indolocarbazole with High Affinity to DNA

• Published in: ChemMedChem 2009-10, Vol.4 (10), p.1641-1648
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; antitumor agents; Apoptosis; Arabinose - analogs & derivatives; Arabinose - chemistry; Arabinose - pharmacology; binding constants; Carbazoles - chemistry; Carbazoles - pharmacology; Cell Line, Tumor; DNA; DNA - chemistry; DNA - drug effects; DNA - metabolism; Female; Humans; indolocarbazoles; Intercalating Agents - chemistry; Intercalating Agents - metabolism; Intercalating Agents - pharmacology; intercalation; Mice; Mice, Inbred Strains; Spectrometry, Fluorescence; Xenograft Model Antitumor Assays
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200900227

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 (1.6×106) M−1≤Ka≤(3.3×106) 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 μM) 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. Fatal attraction: Novel compound 12‐(α‐L‐arabinopyranosyl)indolo[2,3‐α]pyrrolo[3,4‐c]carbazole‐5,7‐dione (see figure) demonstrates remarkable potency against cultured tumor cells and transplanted animal tumors. These effects are associated with the formation of high affinity intercalative complexes between the compound and double‐stranded DNA molecules.