Formation of Human Telomeric G‐quadruplex Structures Induced by the Quaternary Benzophenanthridine Alkaloids: Sanguinarine, Nitidine, and Chelerythrine

Abstract

The ligands which can facilitate the formation and stabilize G‐quadruplex structures have attracted enormous attention due to their potential ability of inhibiting the telomerase activity and halting tumor cell proliferation. It is noteworthy that the abilities of the quaternary benzophenanthridine alkaloids (QBAs), the very important G‐quadruplex binders, in inducing the formation of human telomeric DNA G‐quadruplex structures, have not been reported. Herein, the interaction between single‐strand human telomeric DNA and three QBAs: Sanguinarine (San), Nitidine (Nit) and Chelerythrine (Che), has been investigated. Although these molecules are very similar in structure, they exhibit significantly different abilities in inducing oligonucleotide d(TTAGGG)4 (HT4) to specific G‐quadruplex structures. Our experimental results indicated that the best ligand San could convert HT4 into antiparallel G‐quadruplex structure completely, followed by Nit, which could transform to mixed‐type or hybrid G‐quadruplex structure partially, whereas Che could only transform to antiparallel G‐quadruplex structure in small quantities. The relative QBAs' inducing abilities as indicated by the CD data are in the order of San>Nit>Che. Further investigation revealed that the G‐quadruplex structures from HT4 induced by QBAs are of intramolecular motif. And only sequences with certain length could be induced by QBAs because of their positive charges which could not attract short chain DNA molecules to close to each other and form intermolecular G‐quadruplex. In addition, the factors that affect the interaction between HT4 and QBAs were discussed. It is proposed that the thickness of the molecular frame and the steric hindrance are the primary reasons why the subtle differences in QBAs' structure lead to their remarkable differences in inducing the formation of the G‐quadruplex structures.

Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes

“…In this work, a set of different DNA sequences (Table 1) representing several nucleic acid structures was used. 16,25,28,42 T20 was used as model for an unfolded single-stranded DNA sequence. As models of dsDNA, the self-complementary sequences Dickerson-Drew dodecamer and a 26-mer hairpin (ds26) were used.…”

“…Xiong et al 48 described three possible binding modes of heterocyclic alkaloids: stacking on the top or bottom Gquartets, groove binding and loop binding. Although it is not possible to assign exact binding mode of interaction from spectroscopic experiments, it seems that there exist ~3 binding sites occupied by molecules of QBA with similar energetic level 42,49 . Enhancement of fluorescence at 620 nm (like intercalation) would be explained by stacking (π-π stacking interaction) of QBA to structure of GQ resulting in low fluorescence quenching by water molecules or other quenchers present in solvent.…”

Fluorescently Sensing of DNA Triplex Assembly Using an Isoquinoline Alkaloid as Selector, Stabilizer, Inducer, and Switch‐On Emitter

“…Our results provide an interesting structural insight into the selective recognition of triplex DNA with various IQAs. Protoberberine IQAs (PAL, BER, EPI, JAT, COP, WOR, and BEU) have nonplanar molecular skeletons owing to saturated ring E, whereas unsaturated ring B in the benzophenanthridine IQAs (SAN, CHE, and NIT) and the unsaturated ring E in COR cause these molecules to have planar skeletons . The results in Figure A reveal conclusively that, in respect to the skeleton conformation, the nonplanar IQAs are less efficient than the planar IQAs in stabilizing and inducing triplex assembly.…”

“…However, even for the IQAs with planar skeletons, CHE should be different from SAN and NIT as a result of the different orientations of the substituent groups. For example, the methoxyl group at the C‐7 position in CHE has been found to be perpendicular to the skeleton plane because of the steric hindrance arising from the hydrogen at the C‐6 position and the methoxyl group at the C‐8 position, as revealed in the poorest binding of CHE with the planar tetrad in the G‐quadruplex structure in comparison with SAN and NIT . Such modification in the molecular structure of CHE also results in relatively poor binding with the duplex DNA .…”

Recent Progress in Fluorescence Signal Design for DNA‐Based Logic Circuits

“…Investigations show that the topology and stabilityo fGquadruplexes depend on many factors, including the length and sequence composition, the size of the loops between the guanines, strand stoichiometry,a nd alignment. [56] Besides, various metal cations, [57] such as K + ,N a + ,P b 2 + ,a nd so forth, and ligands, such as thrombin, [58] hemin, [59] berberine, [50b] sanguinarine, [60] and so forth, have the ability to facilitate the formation of certain G-quadruplexeso rt or egulate it from one subtype to another,p roviding abundant inputc andidates and sufficient space forDNA sequence design. [61] Pei and co-workers [62] designed aG T-rich ssDNA, GT24, which could be induced to form various structures by different inputting stimuli,s uch as ap arallel G-quadruplex induced by K + and thrombin, an antiparallel G-quadruplex induced by Pb 2 + ,a nd T-Hg 2 + -T ds-DNA induced by Hg 2 + .E mploying NMM as the probe to indicatet he formation of ap arallel G-quadruplex, they succeeded in implementing as eries of Boolean logic functions, including NOT,N OR, OR, and AND gate, in an easy way.…”