Novel fluorinated benzimidazole-based scaffolds and their anticancer activity in vitro

• Published in: Journal of fluorine chemistry 2016-08, Vol.188 (C), p.99-109
• Main Authors: Bhambra, Avninder S., Edgar, Mark, Elsegood, Mark R.J., Horsburgh, Lynne, Kryštof, Vladimír, Lucas, Paul D., Mojally, Mariam, Teat, Simon J., Warwick, Thomas G., Weaver, George W., Zeinali, Fatemeh
• Format: Article
• Language: English
• Subjects: Anticancer activity; Benzimidazole; C-F activation; Fluorinated drug scaffolds; SNAr substitution
• ISSN: 0022-1139; 1873-3328
• DOI: 10.1016/j.jfluchem.2016.06.009

[Display omitted] Linked and macrocyclic fluoropyridylbenzimidazoles exhibit anti-cancer activity against breast carcinoma MCF-7 and leukemia K562 cell lines. •A library of twelve fluoroaryl benzimidazoles prepared.•SNAr strategy allows rapid assembly of linked and macrocyclic heterocyclic structures.•X-ray crystal structures of fluorinated 21- and 24-membered macrocycles.•Three compounds exhibit micromolar inhibition of K-562 and MCF-7 cell lines.•Two compounds activate caspases leading to apoptosis. A small library of twelve, structurally diverse, fluoroaryl benzimidazoles was prepared using a simple synthetic strategy employing SNAr reactions. This allowed rapid assembly of heterocyclic structures containing linked and tethered fluoroaryl benzimidazoles. X-ray crystal structures of seven compounds were obtained including those of two macrocyclic compounds containing 21- and 24-membered rings. Three tethered fluoroaryl benzimidazole derivatives demonstrated micromolar inhibition against K-562 and MCF-7 cell lines. These compounds, in addition to 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-ylsulfanyl-1H-benzimidazole, also demonstrated micromolar inhibition against G361 and HOS cell lines. Two of the compounds were found to activate caspases leading to apoptosis.