Insights from Binding on Quadruplex Selective Carbazole Ligands

Abstract

Polymorphic G-quadruplex (G4) secondary DNA structures have received increasing attention in medicinal chemistry owing to their key involvement in the regulation of the maintenance of genomic stability, telomere length homeostasis and transcription of important proto-oncogenes. Different classes of G4 ligands have been developed for the potential treatment of several human diseases. Among them, the carbazole scaffold with appropriate side chain appendages has attracted much interest for designing G4 ligands. Because of its large and rigid π-conjugation system and ease of functionalization at three different positions, a variety of carbazole derivatives have been synthesized from various natural or synthetic sources for potential applications in G4based therapeutics and biosensors. Herein, we provide an updated close-up of the literatures on carbazole-based G4 ligands with particular focus given on their detailed binding insights studied by NMR spectroscopy. The structure-activity relationships and the opportunities and challenges of their potential applications as biosensors and therapeutics are also discussed. This review will provide an overall picture of carbazole ligands with remarkable G4 topological preference, fluorescence properties and significant bioactivity; portraying carbazole as a very promising scaffold for assembling G4 ligands with a range of novel functional applications.

Indole-Based Tubulin Inhibitors: Binding Modes and SARs Investigations

“…Several studies have shown that carbazole derivatives have significant biological activities, such as anticancer, psychotropic, anti-inflammatory, anti-histaminic and anti-biotic activities [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. Mahanine [ 58 ] and ellipticine [ 59 ] are two carbazole-based nitrogen heterocycle products extracted from nature with excellent anti-cancer activity.…”

Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective c-MYC Transcription Repressors Targeting the Promoter G-Quadruplex

“…There are still several challenges for discovering an ideal ligand of c-MYC G4 to treat cancer both in vitro and in vivo through structural optimization. − Recently, carbazole and imidazole derivatives were reported to exhibit strong binding affinities to c-MYC G4. − We previously developed a specific c-MYC G4 ligand IZCZ-3 ( 1 ) with a carbazole and imidazole scaffold, which inhibited c-MYC expression, leading to excellent antitumor activities in vitro and in vivo . However, this compound is also accompanied by poor solubility and lacks selective activity for cancer cells.…”

“…The synthetic routes of key amine intermediates (35−37, 40, 41, 43, 48−51) and azide intermediates (30,31,53) are illustrated in Scheme 1A. To obtain the synthetic blocks of R groups with sugar, we first synthesized the synthetic blocks of the carbohydrate part (R′ group) according to a previously reported method, including intermediates 25−31, which were derived from starting materials 18−20 in high yields.…”

Morphology optimization of side-chain copolymers yields a ternary memory device with high stability and reproducibility

“…Herein, carbazole (Cz) units, widely explored in memory research, were also introduced as the functional pendant owing to their large conjugated planarity and hole transporting characteristics. [28][29][30] Meanwhile, nitro substituted carbazoles (NCzs) were designed as electron-acceptors in consideration of the same sp 2 hybrid nitrogen atoms in Cz/NCz units (Fig. 1).…”