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. 2023 Mar 30;9(4):e14954. doi: 10.1016/j.heliyon.2023.e14954

Interaction of isoquinoline alkaloids with pyrimidine motif triplex DNA by mass spectrometry and spectroscopies reveals diverse mechanisms

Zhaoyang Xie a,1, Sunuo Zhang d,1, Yi Wu a, Jinling Liang b, Wenbin Yao b, Ruoning Qu c, Xiaole Tong e, Guang Zhang c,∗∗, Hongmei Yang a,∗
PMCID: PMC10112036  PMID: 37082631

Abstract

Isoquinoline alkaloids represent an important class of molecules due to their broad range of pharmacology and clinical utility. Prospective development and use of these alkaloids as effective anticancer agents have elicited great interest. In this study, in order to reveal structure-activity relationship, we present the characterization of bioactive isoquinoline alkaloid-DNA triplex interactions, with particular emphasis on the sequence selectivity and preference of binding to the two types of DNA triplexes, by electrospray ionization mass spectrometry (ESI-MS) and various spectroscopic techniques. The six alkaloids, including coptisine, columbamine, epiberberine, berberrubine, jateorhizine, and fangchinoline, were selected to explore their interactions with the TC and TTT triplex DNA structures. Berberrubine, fangchinoline, coptisine, columbamine, and epiberberine have preference for TC rich DNA sequences compared to TTT rich DNA triplex based on affinity values in MS. The experimental results from different fragmentation modes in tandem MS, subtractive and hyperchromic effects in UV absorption spectra, fluorescence quenching and enhancement in fluorescence spectra, and strong conformational changes in circular dichroism (CD) hinted that the interaction between isoquinoline alkaloid-TC/TTT DNA had diverse mechanisms including at least two different binding modes: the electrostatic binding and the intercalation binding. Interestingly, columbamine, berberrubine, and fangchinoline can stabilize TTT triplex as inferred from optical thermal melting profiles, while it was not the case in TC triplex. These results provide new insights into binding of isoquinoline alkaloids to pyrimidine motif triplex DNA.

Keywords: Triplex DNA, Isoquinoline alkaloids, Interaction, Mass spectrometry, Spectroscopy

1. Introduction

Felsenfeld and co-workers first observed the formation of triplex DNA structures in 1957 [1]. A triplex DNA is formed by the binding of a single stranded triplex forming oligonucleotide (TFO) in the major groove of a double stranded DNA through Hoogsteen base pairing with the purine residues [2]. Each nucleic acid segment forming three strands of DNA consists of all purine or all pyrimidine bases. Triplex DNA in treating a wide range of diseases including cancer and viral infections [[3], [4], [5], [6]], suppression of gene expression [7,8] and for the creation of various artificial nanostructures [9] has been suggested, being ascribed to the high specificity and affinity of TFOs. Therefore, resurgence on the structure and stability of DNA triplexes has sparked renewed recent interest. However, the stability of a triplex is lower compared to a duplex, which has limited their practical applications under physiological conditions [10]. On the basis of the potential of DNA triplexes to serve as powerful tools in various biotechnological and medicinal applications, great efforts have been put in enhancing the stability of triplexes, involving employing chemical modifications at the nucleobase [11,12], sugar [13], or on the backbone [14]. Other strategies such as use of intercalators covalently linked to the TFO [15] and small molecules to form noncovalent complexes [16,17], can also stabilize DNA triplexes.

Alkaloids represent an essential resource with versatile significance and utilities, and play a key role in drug discovery [18]. Recently, attention has been drawn towards the promising and wide ranging therapeutic potential of isoquinoline alkaloids [[19], [20], [21]]. DNA and RNA have been thought to be the targets in manifesting their anticancer activities, and, accordingly, the binding properties of these alkaloids to them have been described in many publications [22,23]. Furthermore, the broad utility of isoquinoline alkaloids for humankind has led to considerable interest in interaction with triplex DNA at the molecular level [[24], [25], [26]]. Many methods have been used to investigate DNA–ligand interactions, such as electrospray ionization mass spectrometry (ESI-MS), ultraviolet–visible (UV) spectroscopy, fluorescence spectroscopy, and circular dichroism (CD) spectroscopy. ESI-MS is an efficient method to investigate the interaction of DNA with a ligand. The full scan MS can not only quickly determine whether ligands bind to DNA, which can directly obtain the stoichiometric ratio of the complex, but also can be used to evaluate the affinity and selectivity of ligands binding to DNA. ESI-MS/MS can be employed to examine the fragmentation patterns of ligand/DNA complexes on the basis of the facts that complexes with different binding modes produced distinct fragmentation patterns upon collision-induced dissociation (CID) [[27], [28], [29]]. UV–Vis absorption spectroscopy is one of the most useful tools for studying the interaction between small molecules and DNA. The subtractive effect indicates the classical insertion binding mode of the small molecules and DNA [30], and the hyperchromic effect demonstrates that small molecules binds to DNA via electrostatic attraction [31]. CD spectroscopy is a useful way for determining binding mode and affinity of ligands and DNA. The weak fluorescence of DNA will limit the use of fluorescence spectroscopy to study the interaction between small molecule ligands and DNA. In general, the fluorescence of ligands themselves or the fluorescence generated after the interaction of fluorescent probe reagents with DNA was used for research [[32], [33], [34]]. Ethidium bromide (EB) is a typical intercalator, which has been shown to have relatively weak effect or no effect on stabilizing DNA triplexes [35]. It was particularly noteworthy that the isoquinoline alkaloids, coralyne and berberine, could stabilize triplex DNA [36,37]. The structural description of the complexes can present key steps in understanding their biological functions. The binding of coptisine, columbamine, epiberberine, berberrubine, jateorhizine, and fangchinoline with DNA triplexes has been found in the extracts of Rhizoma coptidis, Phellodendron chinense Schneid cortexe, and Stephania tetrandra S. Moore in our previous researches [27,38]. In order to gain more insight into their DNA triplex binding ability, this work focuses on sequence selectivity and binding mode. We investigated their interaction with the TC and TTT triplex DNA structures to understand the structural and sequence diversities by ESI-MS in conjunction with UV spectroscopy, fluorescence spectroscopy, and CD spectroscopy.

2. Experimental

2.1. Materials

Coptisine, columbamine, epiberberine, berberrubine, jateorhizine, fangchinoline, and ethidium bromide (EB) were acquired from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). All the alkaloid standards (1 mM) were prepared in 20 mM ammonium acetate solution (pH 5.5). The TC triplex DNA consists of d(CCTTCCTCTTCTCT) (T1), d(AGAGAAGAGGAAGG) (T2), and d(TCTCTTCTCCTTCC) (T3). And the TTT triplex DNA was formed by d(TTTTTTTTTTTTTT) (T1), d(AAAAAAAAAAAAAA) (T2), and d(TTTTTTTTTTTTTT) (T3). All the oligonucleotides used were bought from Takara Biotechnology (Dalian, China). Methanol is of HPLC grade (Fisher, Pittsburgh, PA, USA). Ultrapure water (specific conductivity, 18.2 MΩ/cm) was produced using a MilliQ device (Millipore, Milford, MA, USA).

2.2. Preparation of nucleic acid and principle of assay

The stock solutions (1 mM) of each single strand were prepared in Milli-Q water. The oligodeoxynucleotides T1, T2 and T3 were mixed at a molar ratio of 1:1:1 in 200 mM NH4OAC (pH = 5.5) solution. The solution was heated at 90°C for 10 min and then slowly cooled to room temperature, followed by keeping the solution at 4 °C overnight to form triplex DNA.

2.3. Direct infusion ESI-MS

The mixture of the triplex DNA and each ligand at the molar ratio of 2:1 in 20 mM ammonium acetate/methanol (80:20, v/v) was infused into an LTQ-XL mass spectrometer (Thermo, San Jose, CA) via a syringe pump at a flow rate of 10 μL/min. The spray voltage and the tube lens offset were set to 3600 V and −180 V, respectively. Nitrogen was used as sheath and auxiliary gases, and their flow rates were set to 54 and 90 L/h, respectively. All the MS data were achieved at the capillary temperature of 250 °C in the negative ion mode.

2.4. UV spectroscopy and thermal denaturation profiles

UV absorbance and UV thermal denaturation measurements were performed using a UV-1102 II ultraviolet spectrophotometer (Techcomp (China) Ltd., China) equipped with a quartz colorimetric vessel of 1 cm pathlength. The absorbance of the mixture of the triplex DNA (1 μM) in a solution containing 50 mM ammonium acetate (pH 5.5) and ligand (2 μM) was measured at a wavelength from 200 to 350 nm. For melting point detection, the stock solutions were diluted to 0.8 μM for triplex DNA and 1.6 μM for the alkaloid solutions. The absorbance of each sample was measured at 260 nm in the temperature range from 15 to 70 °C at the rate of 1.0 °C/min. The melting temperatures were determined from the absorbance versus temperature derivative curve.

2.5. Fluorescence spectroscopy

All fluorescence measurements were carried out on an Agilent 1100 FLD spectrofluorimeter (Agilent Technologies, Waldbronn, America) using a quartz cuvette of 1 cm path length. The excitation and emission wavelengths were set at 520 and 605 nm, respectively. Fixed concentration of EB (3 μM) was titrated with increasing amounts of the triplex DNA solution until fluorescence intensity did not increase. The half of the highest concentration of the triplex DNA was used for further analysis. The fluorescence spectra were recorded by varying the ligand concentration while keeping the concentration ratio of DNA to EB at room temperature.

2.6. Circular dichroism

CD spectroscopies were recorded by a MOS-450 circular dichroism spectropolarimeter (Bio-Logic, Claix, France) using a 1-mm optical path length quartz cuvette at room temperature. Samples were measured at the wavelength from 200 to 350 nm with a 0.5 nm step resolution and averaged over 3 scans recorded at a rate of 200 nm/min. Background spectrum of 20 mM ammonium acetate solution (pH 5.5) was subtracted from each mixture of 20 μM triplex DNA and ligand.

3. Results and discussion

3.1. Binding degrees of DNA triplex-isoquinoline alkaloid complexes detected by ESI-MS and fragmentation pattern analysis by MS2

The complexes formed by six standards with the TC/TTT triplex DNA are shown in Fig. 1A–L. The relative binding degrees (RBDs) of the ligands to the triplex DNA are evaluated by the values of fraction of bound DNA. The calculation was performed using the following equation:

fractionofboundDNA=I(1:1)+I(2:1)+I(3:1)+…I(DNA)+I(1:1)+I(2:1)+I(3:1)+… (1)

where I (DNA) represents the relative abundance of free triplex DNA, and I (n:1) (n = 1, 2, 3 …) represents the relative abundance of the ligand-triplex DNA complex in the mass spectra.

Fig. 1.

Fig. 1

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Representative full scan mass spectra of the mixture of 10 μM TC triplex DNA binding with 5 μM (A) coptisine, (B) columbamine, (C) epiberberine, (D) berberrubine, (E) jateorhizine, and (F) fangchinoline as well as 10 μM TTT triplex DNA binding with 5 μM (G) coptisine, (H) columbamine, (I) epiberberine, (J) berberrubine, (K) jateorhizine, and (L) fangchinoline in 20 mM NH4OAc (PH 5.5) and 20% CH3OH. [T + M]: the complex of triplex DNA binding with ligand, T: the target triplex DNA, ST: single-strand oligonucleotide of the target triplex DNA. (M) Histogram of the RBDs of six isoquinoline alkaloids toward the two DNA triplexes (n = 6). t-test by using SPSS was employed to determine statistical significance. *P < 0.05; ns: no significance.

The complex formed by these ligands interacting with TC or TTT triplex DNA can be directly observed from the full scan MS (Fig. 1A–L), indicating that these standards can interact with the target DNA. The RBD values of the six ligands binding to the TC and TTT triplex DNA respectively calculated using Equation (1), are shown in Fig. 1M. It was clear that the affinity of the alkaloids to the TC triplex DNA varied in the order berberrubine > fangchinoline » coptisine > columbamine » epiberberine > jateorhizine. The binding affinity values for berberrubine-TTT triplex DNA interaction were remarkably higher than those for other isoquinoline alkaloid complexes (t-test, P < 0.05), revealing a remarkably high preference of berberrubine for the TTT triplex DNA. The affinity of the six isoquinoline alkaloids except jateorhizine to different DNA triplexes varied in the order TC triplex DNA > TTT triplex DNA, demonstrating that the five alkaloids have preference for TC rich DNA sequences. The results from ESI-MS indicated that the sequence selectivity of jateorhizine was not significant (Fig. 1M).

In an attempt to predict binding modes of the six isoquinoline alkaloids to triplex DNA, CID experiments were carried out, as shown in Fig. 2. It was clearly seen that the fragmentation pathway was characterized by the destruction of the triplex DNA structures and the retention of ligands on the single-stranded nucleic acid (Fig. 2A–C, E, G–I, and K). In comparison with MS/MS spectra of EB/DNA triplex complexes (Fig. S1A and B), similar fragmentation patterns were observed, indicating that the 4 isoquinoline alkaloids bond to the two DNA triplexes probably via an intercalative binding mode.

Fig. 2.

Fig. 2

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Representative ESI-MS/MS spectra of the complexes of the 10 μM TC triplex DNA binding with 5 μM (A) coptisine, (B) columbamine, (C) epiberberine, (D) berberrubine, (E) jateorhizine, (F) fangchinoline, and the 10 μM TTT triplex DNA binding with 5 μM (G) coptisine, (H) columbamine, (I) epiberberine, (J) berberrubine, (K) jateorhizine, (L) fangchinoline in 20 mM NH4OAc (PH 5.5) and 20% CH3OH. Annotation is performed similar to Fig. 1.

Intriguingly, in the case of berberrubine and fangchinoline, the relevant complexes dissociated predominantly by the loss of a berberrubine/fangchinoline molecule, leaving the intact triplex DNA (Fig. 2D and F), and strand separation from the intact triplex DNA resulting in the single strand T3 (Fig. 2D, F, J, and L). The fragmentation pattern observed was in agreement with our previous report where the [d(TGGGGT)]4–fangchinoline/tetrandrine complex was dissociated by the ligand loss and an end-stacking binding mode was suggested [39]. Though the specific DNA-binding mode cannot be directly deduced from the tandem mass spectra of the complexes, some valuable information was provided.

3.2. Binding modes and stabilization of the complexes depend on DNA sequences and alkaloid structures by UV–Vis analysis

The changes of absorbance of the TC/TTT triplex DNA after doping with the alkaloids are depicted in Fig. 3. As for the TC triplex DNA, the UV–Vis absorption wavelength showed red-shift, and the absorbance increased with the addition of fangchinoline, columbamine, and coptisine (Fig. 3A, B, and F), which suggested that these molecules bond to DNA via electrostatic attraction and thereby causing a damage to the structure of TC triplex DNA. While the absorbance decreased with the addition of berberrubine, jateorhizine, and epiberberine (Fig. 3C, D, and E), suggesting an intercalating binding mode. In the case of TTT triplex DNA, the UV–Vis absorption wavelength showed red shift, and the absorbance increased with the addition of six ligands, suggesting that these molecules bind to TTT triplex DNA by electrostatic attraction (Fig. 3G–L). Taking these results into consideration, one can conclude that binding modes of the same molecule and different DNA triplexes also depend on DNA sequence.

Fig. 3.

Fig. 3

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UV–Vis absorption spectra of 1 μM TC triplex DNA in the absence and presence of 2 μM (A) coptisine, (B) columbamine, (C) epiberberine, (D) berberrubine, (E) jateorhizine, (F) fangchinoline, and 1 μM TTT triplex DNA binding to 2 μM (G) coptisine, (H) columbamine, (I) epiberberine, (J) berberrubine, (K) jateorhizine, (L) fangchinoline.

Could one or some of these six alkaloids stabilize triplex DNA? In order to answer this question, thermal-melting profiles of the two triplexes and their complexes with the alkaloids at molar ratio of 1:2 were investigated since melting-stabilization data could give indication of the extent of stabilization effected by the binding interaction [40]. The comparative thermal melting profiles are displayed in Fig. 4. No significant change was observed for the melting temperature (Tm) of TC DNA triplex in the absence or presence of the six alkaloids (Fig. 4A–F), manifesting no effect for the six alkaloids on the stability of TC DNA triplex. In case of TTT DNA triplex, the extent of stabilization of the third strand was more pronounced with columbamine, berberrubine, and fangchinoline with △Tm values of 5, 3, and 4 °C, respectively (Fig. 4H, J, and L), compared to coptisine, epiberberine, and jateorhizine where almost no change was observed on Tm (Fig. 4G, I, and K). These results suggest specific stabilization of the TTT triplex structure by the three alkaloids including columbamine, berberrubine, and fangchinoline, illustrating the important roles of chemical structure diversity and DNA sequence in their interaction.

Fig. 4.

Fig. 4

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Melting denaturation curves of 0.8 μM TC triplex DNA in the absence and presence of 1.6 μM (A) coptisine, (B) columbamine, (C) epiberberine, (D) berberrubine, (E) jateorhizine, (F) fangchinoline, and 0.8 μM TTT triplex DNA binding with 1.6 μM (G) coptisine, (H) columbamine, (I) epiberberine, (J) berberrubine, (K) jateorhizine and (L) fangchinoline.

3.3. Fluorescence quenching studies of interaction between DNA triplexes and isoquinoline alkaloids in the presence of EB

Here, ethidium bromide (EB), a classical intercalator [40], was used as a sensitive probe for DNA to study the binding ligands with TC and TTT DNA triplexes. By keeping the concentration of EB at 3 μM and varying DNA concentration in the reaction mixtures, the fluorescence intensities of the two systems were studied and showed enhanced intensities until 12.36 μM TC and TTT DNA triplexes (Fig. S2A and B). Based on the results, TC/TTT DNA concentration in the experiment was selected as 6.18 μM, that is, the ratio of DNA to EB was 2.06:1.

Fig. 5 exhibits the emission spectra of EB-bound triplex DNA in the presence of the six alkaloids. Successive addition of columbamine, epiberberine, berberrubine, and fangchinoline (Fig. 5B–D, and F) to EB–TC DNA complex as well as epiberberine and berberrubine (Fig. 5I and J), to EB–TTT DNA complex resulted in progressive quenching of fluorescence at 605 nm. The results demonstrated that they could bind to the target DNA effectively in an intercalative binding mode according to the criterion: an intercalative binding mode for the interaction of a target with DNA when the fluorescence intensity of EB-DNA system decreased by 50% and Ctarget/CDNA < 100. The fluorescence change, in other cases, is indicative of strong association of these alkaloids to the triplex but not in the classical intercalation binding mode. The specific mode of these small molecules binding to target DNA needs further investigation (Fig. 5A, E, G, H, K, and L).

Fig. 5.

Fig. 5

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The fluorescence spectra of TC triplex DNA-EB complex by adding various concentrations of (A) coptisine, (B) columbamine, (C) epiberberine, (D) berberrubine, (E) jateorhizine, (F) fangchinoline, and TTT triplex DNA-EB complex by adding various concentrations of (G) coptisine, (H) columbamine, (I) epiberberine, (J) berberrubine, (K) jateorhizine, (L) fangchinoline. Cligand = 0, 1.5, 8.1, 14.8, 30.6, 52 μM.

3.4. Circular dichroism spectroscopy analysis of the complexes

The CD spectra of DNA in the presence of the ligands were illustrated (Fig. 6). Similar results were obtained for each ligand. It is clear from Fig. 6 that the intensities of the bands are increased with varying degrees in the presence of increasing concentrations of ligands in both the positive and negative bands. The two conservative CD bands at 280 nm because of base stacking and at 225 nm due to the right-handed helicity were detected in Fig. 6, which may show stabilization of the right-handed B form of the targeted DNA [41]. On account of observation of negative CD curves, the interaction of all the ligands with DNA would be inferred as an intercalative-binding mode according to the previous report (Fig. 6A–L) [42].

Fig. 6.

Fig. 6

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CD spectra for 20 μM TC triplex DNA in the presence of increasing concentrations of (A) coptisine, (B) columbamine, (C) epiberberine, (D) berberrubine, (E) jateorhizine, (F) fangchinoline (0 nM–500 μM), and 20 μM TTT triplex DNA in the presence of increasing concentrations of (G) coptisine, (H) columbamine, (I) epiberberine, (J) berberrubine, (K) jateorhizine, and (L) fangchinoline (0 nM–500 μM).

4. Conclusions

This study, for the first time, presents the comparative binding data of complexation of the six isoquinoline alkaloids, coptisine, columbamine, epiberberine, berberrubine, jateorhizine, and fangchinoline, to the TC and TTT DNA triplexes by ESI-MS/MS, UV–Vis absorption spectroscopy, fluorescence spectroscopy, and CD spectroscopy. All the data unequivocally accommodated diverse mechanisms for interaction between the isoquinoline alkaloids and TC/TTT DNA triplexes. At least, electrostatic attraction and intercalative-binding modes were observed in our study. These differences in the interaction profiles highlight the importance of diversities of small molecule structures and triplex DNA sequences. More importantly, UV melting denaturation assay revealed that the three isoquinoline alkaloids including columbamine, berberrubine, and fangchinoline enhanced the stability of the TTT triplex structure. Remarkable advancement was made here in our understanding of isoquinoline alkaloids-DNA triplex interactions due to data by multiple spectroscopies. A complete understanding of these aspects will permit the development of novel isoquinoline alkaloids-based therapeutic agents with higher efficacy.

Author contribution statement

Zhaoyang Xie: Performed the experiments; Wrote the paper.

Sunuo Zhang: Analyzed and interpreted the data; Wrote the paper.

Yi Wu, Wenbin Yao: Performed the experiments.

Jinling Liang, Ruoning Qu: Analyzed and interpreted the data.

Xiaole Tong: Contributed reagents, materials, analysis tools or data.

Guang Zhang: Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data.

Hongmei Yang: Conceived and designed the experiments; Analyzed and interpreted the data; Wrote the paper.

Funding statement

Dr. Hongmei Yang was supported by the Health Technology Innovation Project of Jilin Province [2021JC075] and the Science and Technology Development Planning Project of Jilin Province [20220508086RC]. Guang Zhang was supported by the Science and Technology Development Planning Project of Jilin Province [20200201580JC] and the Project of the Education Department of Jilin Province [JJKH20201055KJ].

Data availability statement

Data will be made available on request.

Declaration of interest’s statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

Appendix

Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2023.e14954.

Contributor Information

Guang Zhang, Email: zhangguang@jlu.edu.cn.

Hongmei Yang, Email: yanghm0327@sina.cn.

Appendix ASupplementary data

The following is the Supplementary data to this article.

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mmc1.docx (87.9KB, docx)

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