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

TY - JOUR

T1 - Methylene-linked bis-phenylbenzimidazoles – a new scaffold to target telomeric DNA/RNA hybrid duplex

AU - Islam, M. K.

AU - Jackson, P. J. M.

AU - Thurston, David Edwin

AU - Rahman, K. M.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048976340&partnerID=8YFLogxK

U2 - 10.1039/c7ob02709e

DO - 10.1039/c7ob02709e

M3 - Article

SN - 1477-0520

VL - 16

SP - 4424

EP - 4428

JO - ORGANIC AND BIOMOLECULAR CHEMISTRY

JF - ORGANIC AND BIOMOLECULAR CHEMISTRY

IS - 24

ER -