DNA sequence-specific ligands: XIII. New dimeric Hoechst 33258 molecules, inhibitors of HIV-1 integrase in vitro

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 degrees 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.

DNA Sequence-Specific Ligands: XII. Synthesis and Cytological Studies of Dimeric Hoechst 33258 Molecules

“…An alteration of absorption spectrum of ( Va ) in the presence of calf thymus DNA indicated the formation of their complex [31]. Chromosomes are identified in most of cytogenetic studies by the pattern of differential staining.…”

DNA sequence-specific ligands. XX. Synthesis, spectral properties, virological and biochemical studies of fluorescent dimeric trisbenzimidazoles DB3P(n)

“…We determined the DB 3 P(n) localization in the DNA groove using the method of circular dichroism (CD) with DNA cholesteric liquid crystal dispersions (preparation of such dispersions was described in [15]) (Fig. 6).…”

“…Previously we described the design and synthesis of several sets of dimeric bisbenzimidazoles [12][13][14][15][16][17], analogues of the dimeric bisbenzimidazole motif of the uorescent AT-speci c Hoechst 33258 dye. These dimeric bisbenzimidazoles were synthesized with the goal of developing AT speci c ligands noncovalently binding to the dsDNA minor groove and occupying nearly one coil.…”

“…These dimeric molecules can bind to two sites, each consisting of two AT pairs separated by two or more nucleotide pairs. Dimeric bisbenzimidazoles were shown to be effective agents in biochemical, virological, and genetic studies [12][13][14][15][16][17].…”

HIV-1 integrase inhibitors: 2007-2008 update

“…Using this approach, a recent study reported the design of inhibitors that could potentially disrupt IN-DNA binding. 105,106 Fluorescent dye Hoechst 33258 is known to bind noncovalently and site-specifically to the minor groove of DNA, but derivatives are insoluble. Attempts at improving the solubility of these DNA binders led to the discovery of potent new IN inhibitors.…”