Benzimidazole-based small molecules as anticancer agents targeting telomeric G-quadruplex and inhibiting telomerase enzyme

Telomeres, crucial for chromosomal integrity, have been related to aging and cancer formation, mainly through regulating G-quadruplex structures. G-quadruplexes are structural motifs that can arise as secondary structures of nucleic acids, especially in guanine-rich DNA and RNA regions. Targeting these structures by small compounds shows promise in the selective suppression of cell growth, opening up novel possibilities for anticancer treatment. A comprehensive investigation of the many structural forms of G-quadruplex ligands is required to create ground-breaking anticancer drugs. Recent research into using specific benzimidazole molecules in stabilizing telomeric DNA into G-quadruplex structures has highlighted their ability to influence oncogene expression and demonstrate antiproliferative characteristics against cancer cells. This review describes the benzimidazole derivative, designed to enhance the stability of the G-quadruplex structure DNA to suppress the activity of telomerase enzyme, exhibiting promising potential for anticancer therapy <b>Benzimidazole-Carbazole Ligands</b>: These molecules incorporate both benzimidazole and carbazole moieties, known for their strong interaction with G-quadruplex DNA, leading to telomerase inhibition. <b>Bis(benzimidazole)pyridine Derivatives</b>: Featuring a pyridine core flanked by two benzimidazole units, these compounds show high affinity for G-quadruplex stabilization, effectively inhibiting telomerase activity. <b>Benzimidazole-1,2,3-Triazole Hybrid Molecules</b>: These hybrids combine benzimidazole with a 1,2,3-triazole ring, potent in stabilizing G-quadruplex DNA and contributing to their role as anticancer agents. <b>Dimeric 1,3-Phenylene-bis(piperazinyl Benzimidazole)</b>: These compounds contain two benzimidazole units linked by a 1,3-phenylene-bis(piperazine) scaffold, effectively binding and stabilizing G-quadruplex DNA structures. <b>Tröger's Base-Benzimidazole Derivatives</b>: Integrating the rigid Tröger's base with benzimidazole units, these derivatives are known for their selective stabilization of G-quadruplex structures. <b>β-Carboline–Benzimidazole Derivatives</b>: Merging the β-carboline scaffold with benzimidazole, these derivatives exhibit potent G-quadruplex binding, leading to telomerase inhibition. <b>Naphthalene Diimide-Linked Bis-Benzimidazole Derivatives</b>: Combining naphthalene diimide with bis-benzimidazole units, these molecules strongly stabilize G-quadruplex DNA, showing significant anticancer potential.○ Shirley, M. <i>Drugs</i> <b>2018,</b> 78, 1277–1284.○ Barman Balfour, J. A.; Goa, K. L. <i>Drugs</i> <b>2001,</b> 61, 631–638.○ Markham, A.; Keam, S. J. <i>Drugs</i> <b>2020,</b> 80, 931–937.○ Kim, E. S. <i>Drugs</i> <b>2017,</b> 77, 2063–2070.○ Wagner, L. M. <i>OncoTargets and therapy</i> <b>2015</b>, 1931–1939. Shirley, M. <i>Drugs</i> <b>2018,</b> 78, 1277–1284. Barman Balfour, J. A.; Goa, K. L. <i>Drugs</i> <b>2001,</b> 61, 631–638. Markham, A.; Keam, S. J. <i>Drugs</i> <b>2020,</b> 80, 931–937. Kim, E. S. <i>Drugs</i> <b>2017,</b> 77, 2063–2070. Wagner, L. M. <i>OncoTargets and therapy</i> <b>2015</b>, 1931–1939. Importance in predicting how small molecules interact with targets like G-quadruplex (G4) DNA. Methods for assessing binding affinity and stability. Binding affinity influences the stability and effectiveness of ligand-DNA interactions. <b>Telomerase Inhibition Assay:</b> Utilizes a modified cell-free system to assess the ability of ligands to inhibit telomerase enzyme activity. IC₅₀ Values Provide quantitative measures of ligand effectiveness in inhibiting telomerase. <b>Cytotoxicity Assessment</b> Cell Line Studies Investigates the cytotoxic effects of ligands on HeLa cells using Annexin V-FITC and PI dual staining assays. Ligand demonstrated the highest cytotoxicity, leading to observable apoptotic features in treated cancer cells.