Methylene-linked bis-phenylbenzimidazoles – a new scaffold to target telomeric DNA/RNA hybrid duplex

Abstract

We report a series of novel methylene-linked bis-phenylbenzimidazoles intercalators that stabilize telomeric DNA/RNA hybrid (tDRH) structures by up to 7.2 °C at a 1 μM ligand concentration while having negligible affinity for DNA/DNA duplexes, although with a low affinity for quadruplex DNA. We have used molecular modelling studies to rationalize this selectivity, concluding that the methylene spacer between the terminal benzimidazole and phenylene moieties plays a key role in facilitating the bis-intercalating process. This scaffold may be used to develop chemical tools or new therapeutics to selectively target the telomeric DNA/RNA duplex without affecting normal genomic DNA.

Synthesis, Antibacterial Activity and Photophysical Properties of Bis-benzamide derivatives

“…It is known that bis-benzamides exhibit various pharmacological activities such as potential metal chelators inhibiting redox activity in Alzheimer's disease [6], anticancer [1,7,8], antiproliferative [9], tyrosyl-DNA phosphodiesterase I−topoisomerase I inhibitors [10], anti-HIV [11] and anti-HCV activities [12] as well as α1-AR receptor [13], acetylcholinesterase [14], Kirsten rat sarcoma 2 viral oncogene homolog− PDEδ [15], thioredoxin reductase [16], glutaminase and glutamate dehydrogenase inhibitors [17]. In addition, methylene-linked bis-phenylbenzimidazoles which stabilize telomeric DNA/RNA hybrids have been reported [18]. Furthermore, bis-benzamides are also useful as intermediate compounds for synthesis of pharmacologically active compounds such as amidoximes [19], lycopodium alkaloids (+)-flabellidine and (−)-lycodine [20] In this study, the synthesis and antibacterial activity of bis-benzamide derivatives were reported.…”