Telomeric DNA and C-myc22 are DNA G-quadruplex (G4)-forming sequences associated with tumorigenesis. Ligands that can facilitate the formation and increase the stabilization of G4 can halt tumor cell proliferation and have been regarded as potential anti-cancer drugs. In the present study, we have investigated the interaction of 11 natural alkaloids with G4 formed by telomeric DNA and C-myc22 sequences. Our results indicated that sanguinarine (San), palmatine (Pal), and berberine (Beb) of the first series (S1) can induce the formation of G4 as well as increase the stabilization ability. Daurisoline (S2-1), O-methyldauricine (S2-2), O-diacetyldaurisoline (S2-3), daurinoline (S2-4), dauricinoline (S2-5), N,N'-dimethyldauricine iodide (S2-6), and N,N'-dimethyldaurisoline iodide (S2-7) of the second series (S2) showed similar stabilization ability. We found that unsaturated ring C, N(+) positively charged centers, and conjugated aromatic rings are key factors to increase the stabilization ability of S1, and we gave some advice on structure modification to S2 through structure-activity study. Besides, we found San and Pal to be cell cycle blocker in G(1). San was speculated to bind to G4 through intercalation or end stacking.
RNA/DNA sequences rich in guanine (G) can form a 4-strand structure, G-quadruplex, which has been extensively researched and observed in mammalian, fungi, and plants, with in vivo existence in eukaryotic cells. Compared with DNA quadruplex, the potential existence of RNA quadruplex appears to be generally rare; however, it is believed by some researchers to be more inevitable in vivo and speculated to play an important role where it exists. Recently, researches concerning the function of G-quadruplexes in RNAs commence, making much progress. However, there is no available review particularly focusing on RNA quadruplex till now as we know. Therefore, we decide to give a review to comprehensively summarize research progress on it. This review highlights the diverse topologies for RNA quadruplex structure and its effect factors; outlines the current knowledge of RNA quadruplex's physiological functions in biological systems, especially in gene expression; and presents the prospects of RNA quadruplex.
Telomeres are important multifunctional nucleoprotein structures located at the ends of eukaryotic chromosomes. Telomerase regulates telomere elongation, and its activity is associated with tumorigenesis. Because the activity of telomerase can be inhibited by G-quadruplex (G4) formation (a four-stranded DNA with stacks of G-quartets formed by four guanines in a planar structure), the role of G4 in cancer therapy has attracted many research interests. We studied the effects of three natural alkaloids-tetrandrine, fangchinoline, and berbamine-on the stability and formation of telomere DNA G4 with circular dichroism melting spectroscopy (melting-CD), variable temperature ultraviolet (melting-UV), proton nuclear magnetic resonance spectroscopy ((1)H NMR), and molecular docking, and examined the relationships among the alkaloid structure and their activities. We further investigated their cytotoxicity with the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) and flow cytometry (FCM). The results demonstrated that alkaloids increased G4 stability and induced its formation, which added structure diversity of G4-ligands. The results showed that -OH at R(1), -OCH(3) at R(2), and [Formula: see text] at R(3) had higher stability than other substituent groups for these alkaloids. We also found a transition of antiparallel to parallel G4 as the temperature increased. The result indicated the possible advantage of parallel G4 in adversity. In addition, the alkaloids demonstrated a moderate cytotoxicity and proved to be cell cycle blocker in the G(1) phase. These alkaloids have revealed promising potentials to be the agents for antitumor therapy.
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