Bisbenzimidazoles

Bisbenzimidazoles (for a review, see Martin 1998) protect cells against ionizing radiation (Denison et al. 1992 Lyubimova et al. 2001). Bisbenzimidazoles such as Hoechst 33258 strongly bind to the minor groove of B DNA (Pjura et al. 1987 in a dodecamer the ATTC region is the preferred intercalating site). 

The binding kinetics and equilibrium constants for five different (A/T)4 DNA sites have been studied in detail, showing that the binding kinetics are complex (Breusegem et al. 2002). Further information as to Hoechst binding by DNA has been obtained by fluorescence spectroscopy (Adhikary et al. 2003) and, to some extent, by atomic force microscopy (Zareie et al. 1998). 

In aqueous solution, intercalated Hoechst 3342 protects DNA against strand breakage beyond OH-scavenging (quenching diameter by Hoechst 3-4 bp Adhikary et al. 1997a). Besides, intercalated Hoechst reacts with OH-induced DNA on the ms time scale. The Hoechst-reactive damaged DNA sites are likely the oxidizing radicals A and G and pyrimidine peroxyl radicals (Table 12.17 for further pulse radiolysis studies on Hoechst in aqueous solution see Adhikary et al. 2000). 

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Polybenzimidazole (PBI) Fibers. Poly(2,2 -(y -phenylene)-5,5 -bisbenzimidazole) [25734-65-0] is a textile fiber marketed by Hoechst-Celanese (11) which does not form Hquid crystalline solutions due to its bent meta backbone monomeric component. PBI has exceUent resistance to high temperature and chemicals. 

Hoechst 33342 [2 -(4-ethoxyphenyl)-5-(4-methyl-l-piperazinyl)-2,5 -bi-IH-benzimidazole Ho342 I], a bisbenzimidazole dye, binds to adenine/thymine-rich regions in the minor groove of DNA. This dye induces apoptosis and inhibits topo 1 activity in vivo. It has been suggested that the destruction of immunoreactive topo I and topo I-DNA complexes or cleavable complexes results in inhibition of topo I activity, a key step in the Hoechst 33342-induced apoptotic process [40]. 

Measurement of DNA solution using bisbenzimidazole dye (Hoechst 33258). http //www.mamgen.tubitak.gov.tr/taylan/protocols/spot 00.txt EtBr spot test for DNA and RNA analysis. 

Dibromo-2,2 -bisbenzimidazoles 692 react with aryl zincates under Negishi coupling conditions to give 4,4 -bisaryl-2,2 -bisbenzimidazoles 693 (Scheme 168). Lower yields were obtained with heteroaryl zincates (2- or 3-pyridyl) <2006OL4989>. Cross-coupling of bromides 694 with phosphonites provided an efficient synthesis of phosphonates 695 <1998TL2797>. 

Abstract Benzimidazole is a biologically important scaffold which displays important biological activities. Recent progress in the synthesis and bioactivity of benzimidazoles is reviewed. New synthetic procedures, including microwave-assisted synthesis, solid phase synthesis, natural product synthesis, and synthesis of bisbenzimidazoles are briefly described. Functionalization and cyclization reactions of benzimidazoles lead to a wide variety of novel benzimidazole structures. Selected bioactivity, such as anti-infective, anti-inflammatory, antitumor and receptor agonist/antagonist activities are presented. 

Bisbenzimidazole derivatives such as Hoechst 33258 (also known as Pibenz-imol) 28 (Fig. 2) is a A/T base pair selective compound that binds in the minor groove of DNA [37]. To investigate its full potential, a number of benzimidazole Hoechst motifs have been synthesized and evaluated for various biological activities [38-40]. 

Mann and coworkers have synthesized a new class of head-to-head bisbenzimidazoles 31 as DNA minor groove binding agents [41]. This new class of 6,6 -bisbenzimidazoles 31 was synthesized in moderate yields by the condensation of 3,3, 4,4 -tetraaminobiphenyl 30 with requisite aromatic aldehyde in nitrobenzene imder reflux for 8-12 hours (Scheme 8). 

Combinatorial parallel synthesis of head-to-tail bisbenzimidazoles 41 has been performed using polymer-immobilized 1,2-diaminobenzenes (Fig. 2). The PEG-bound diamines were hf-acylated at the primary aromatic amino group with 4-fluoro-3-nitrobenzoic acid. The substituted amides were cy-clized to benzimidazoles under acidic conditions. Successive reduction and cyclization with various aldehydes yielded 5-(benzimidazol-2-yl)benzimid-azoles. Finally, the desired products 41 were released from the polymer support to afford the bisbenzimidazoles in good yields and with high purity [46]. 

Using polymer-immobilized liquid phase synthesis and controlled microwave irradiation, trisubstituted bisbenzimidazoles have been prepared and released with good yield and purity [77]. Furthermore, a wide range of benzimidazole derivatives have been synthesized with excellent yields and purities by simple washing and filtration using liquid phase synthesis on a soluble polymer support [78]. 

In addition, the alkyl-linked bisbenzimidazole 135 [115] and thiazolyl-benzimidazole-4,7-diones 136 [116] exhibited cytotoxic activity against tumor cell lines (Fig. 12). 

Hypoxia can now be detected and quantified by microelectrodes and the binding of reactive, reduced metabolites of nitroimidazoles, which reflect oxygen levels (because the radical-anion reduction intermediate is oxygen reactive) [30]. A new fibre-optic probe for tissue oxygenation, now available commercially, relies on measurements of emission from a ruthenium probe, which has an oxygen-dependent excited-state lifetime [31]. Acute or fluctuating hypoxia, which has features in common with ischaemia/reperfusion and therefore with myocardial infarction and stroke, can be detected by vascular stains such as bisbenzimidazole intercalators with different fluorescent characteristics. These can be administered intravenously a few minutes apart ... 

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