DNA sequence-specific ligands: XIII. New dimeric Hoechst 33258 molecules,inhibitors of HIV-1 integrase in vitro |
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Authors: | A V Gromyko V I Salyanov S A Strel’tsov V A Oleinikov S P Korolev M B Gottikh A L Zhuze |
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Institution: | (1) Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, ul. Vavilova 32, Moscow, 119991, Russia;(2) Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia;(3) Belozersky Institute of Physicochemical Biology and Faculty of Chemistry, Moscow State University, Vorob’evy gory, Moscow, 119992, Russia |
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Abstract: | Dimeric Hoechst 33258 molecules dimeric bisbenzimidazoles (DBBIs)] that, upon binding, occupy one turn of the B form of DNA in the narrow groove were constructed by computer simulation. Three fluorescent DBBIs were synthesized; they consist of two bisbenzimidazole units tail-to-tail linked to phenolic hydroxy groups via penta-or heptamethylene or tri(ethylene glycol) spacers and have terminal positively charged N,N-dimethylaminopropyl carboxamide groups in the molecule. The absorption spectra of the DBBIs in the presence of different DNA concentrations showed a hypochromic effect and a small shift of the absorption band to longer wavelengths, which indicated the formation of a complex with DNA. The presence of an isobestic point in the spectrum indicates the formation of one type of DBBI-DNA complexes. The interaction of DBBIs with DNA was studied by CD using a cholesteric liquid-crystalline dispersion (CLD) of DNA. The appearance of a positive band in the absorption region of ligand chromophores in the CD spectrum of the DNA CLD indicates the formation of a DBBI-DNA complex in which ligand chromophores are arranged at an angle close to 54° relative to the helix axis of DNA, which suggests the localization of the DBBI in the narrow groove of DNA. All the DBBIs were found to be in vitro inhibitors of HIV-1 DNA integrase in the 3′-processing reaction, and, of the three DBBIs, two dimers inhibit HIV-1 integrase even in submicromolar concentrations. |
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Keywords: | DNA HIV-1 DNA integrase dimeric Hoechst 33258 molecules inhibitors molecular modeling narrow-groove ligand optical methods of analysis synthesis |
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