Naphthalenediimide-Linked Bisbenzimidazole Derivatives as Telomeric G-Quadruplex-Stabilizing Ligands with Improved Anticancer Activity

ACS Omega
Souvik SurVibha Tandon

Abstract

Human telomeric G-quadruplex DNA stabilization has emerged as an exciting novel approach for anticancer drug development. In the present study, we have designed and synthesized three C2-symmetric bisubstituted bisbenzimidazole naphthalenediimide (NDI) ligands, ALI-C 3 , BBZ-ARO, and BBZ-AROCH 2 , which stabilize human telomeric G-quadruplex DNA with high affinity. Herein, we have studied the binding affinities and thermodynamic contributions of each of these molecules with G-quadruplex DNA and compared the same to those of the parent NDI analogue, BMSG-SH-3. Results of fluorescence resonance energy transfer and surface plasmon resonance demonstrate that these ligands have a higher affinity for G4-DNA over duplex DNA and induce the formation of a G-quadruplex. The binding equilibrium constants obtained from the microcalorimetry studies of BBZ-ARO, ALI-C 3 , and BBZ-AROCH 2 were 8.47, 6.35, and 3.41 μM, respectively, with h-telo 22-mer quadruplex. These showed 10 and 100 times lower binding affinity with h-telo 12-mer and duplex DNA quadruplexes, respectively. Analysis of the thermodynamic parameters obtained from the microcalorimetry study suggests that interactions were most favorable for BBZ-ARO among all of the synthesize...Continue Reading

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Citations

Dec 19, 2018·Chemistry, an Asian Journal·Antony Wing Hung Ng, Ho Yu Au-Yeung
May 1, 2019·Medicinal Chemistry·Smita VermaS J S Flora
Aug 25, 2020·Chemistry of Heterocyclic Compounds·Andrey M ZhirovIvan V Borovlev

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Methods Mentioned

BETA
flow cytometry
NMR
Assay
FRET
isothermal titration calorimetry
column chromatography
chips
electrophoresis
FACS

Software Mentioned

Origin
Chimera
Amber
VMD
AutoDock4
Micro Cal Origin
Glide
BIA
Auto docks
Maestro

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