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

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-C3, BBZ-ARO, and BBZ-AROCH2, 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-C3, and BBZ-AROCH2 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 synthesized compounds. The ΔGfree obtained from molecular mechanics Poisson–Boltzmann surface area calculations of molecular dynamics (MD) simulation studies suggest that BBZ-ARO interacted strongly with G4-DNA. MD simulation results showed the highest hydrogen bond occupancy and van der Waals interactions were between the side chains of BBZ-ARO and the DNA grooves. A significant inhibition of telomerase activity (IC50 = 4.56 μM) and induced apoptosis in cancer cell lines by BBZ-ARO suggest that this molecule has the potential to be developed as an anticancer agent.

Porous Polymer Bearing Polyphenolic Organic Building Units as a Chemotherapeutic Agent for Cancer Treatment

“… 6 Apoptosis is an efficient programmed regulation of cellular homeostasis defined by cell biology. 7 Reactive oxygen species (ROS) act as a crucial factor by working as a messenger in a cellular-signaling system to alarm apoptosis. 8 The equilibrium of ROS and the antioxidant is a prime factor, and any alteration of these two causes various cellular harms, leading to inflammatory diseases and carcinogenesis.…”

Benzimidazole based derivatives as anticancer agents: Structure activity relationship analysis for various targets

“…Sur et al [93] synthesized three bi‐substituted bis‐benzimidazole naphthalene diimide ligands, that stabilized the human g‐quadruplex DNA (telomeric) with strong (high) affinity. Studies revealed that treatment with compound 71 resulted in considerable inhibition of telomerase activity (IC 50 = 4.56 μM) and induced apoptosis in cancer cell‐lines with minimal cytotoxic activity in normal HEK293T cells.…”

Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential

“…Compound 16 was also found to inhibit tumor growth in a mouse xenograft model of cervical squamous cancer [ 216 ]. A disubstituted bisbenzimidazole naphthalenediimide (NDI) ligand BBZ-ARO, was reported to possess high telomeric G4 affinity, which could inhibit telomerase enzyme activity and caused G2/M arrest subsequently inducing apoptosis in cells with a good therapeutic index [ 217 ]. Divalent cationic naphthalene diimide ligands have been shown to selectively bind with telomeric G4 ligand and some of them could specifically kill cancer cells while having very less effect on normal cells [ 218 ].…”