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. 2024 Oct 15;15(11):1866–1874. doi: 10.1021/acsmedchemlett.4c00289

Promoting Apoptosis in MCF-7 Cells via ROS Generation by Quinolino-triazoles Derived from One-Pot Telescopic Synthesis

Joydip Mondal †, Tiasha Dasgupta ‡, Rakesh R Panicker †, Venkatraman Manickam ‡, Arup Sinha †, Akella Sivaramakrishna †,*
PMCID: PMC11571024  PMID: 39563819

Abstract

graphic file with name ml4c00289_0006.jpg

Inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) facilitates potent antiangiogenic and anticancer responses. In this regard, the development of effective pharmacophores, i.e., quinoline-based triazole derivatives 6a–j, by a one-pot telescopic approach is our focus. Among all of them, 6f, possessing amide and cyanide substituents, displayed the highest binding ability with VEGFR-2, having high affinity of −8.9 kcal/mol. Further, 6f and 6g (containing amide and bromo groups) exhibited a wide spectrum of anticancer activities due to the presence of active oxidative stress inducers, with cytotoxicity values of 10 ± 0.2 and 12 ± 0.6 μM, respectively. Apoptosis analysis demonstrated the involvement of 6f and 6g in mitochondrial damage and the loss of mitochondrial membrane potential (ΔΨm). Intercellular localization of 6f/6g in MCF-7 revealed the presence of 6g in the cytoplasm along with an increase in ROS production and a reduction in MMP, proving the ability of 6g to target mitochondria.

Keywords: Quinolino-triazoles, synthesis, ROS, MMP, apoptosis, MCF-7, VEGFR

Introduction

The medical community puts forth huge efforts to discover a cure for cancer, a disease that may be the source of darkness in people’s lives and ultimately result in death. Uncontrolled cell signaling events of cancer produce aberrant cell proliferation, followed by rapid mortality, affecting the entire system.1,2 Breast cancer is the most prevalent and number one cause of morbidity among female cancer deaths globally, although rarely it can also manifest in men.

Endocrine therapy through estrogen signaling has been a long-time target in treating non-TNBC breast cancer types. Interfering mechanisms include estrogen synthesis and/or preventing estrogens from binding to the estrogen receptor (ER) in the binding pocket.3 While aromatase (the enzyme that produces estrogen) inhibitors are very important in therapy, unfortunately, they can act as agonists to estrogen, thereby increasing the risk of endometrial cancer and/or stroke in cancer patients.4 Thus, it is important to look into diverse target types when targeting cancer.

Significant efforts are also underway toward controlling breast cancer through targeting receptor tyrosine kinases (RTKs). Thus, numerous investigations have been carried out targeting the overexpression of many receptor tyrosine kinases (RTKs), mainly epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR), in both primary and metastatic breast cancers.5

Due to its relevance in tumor angiogenesis and metastasis, VEGF/VEGFR-2 disruption provides strong targeted antitumor targeting measures.6,7 Various VEGFR-2 targeted inhibitors, either alone or in conjunction with other chemotherapies, have received clinical authorization because they lead to a better prognosis for cancer patients.8 Researchers further employ various molecular functionalization techniques to modify the structural features of existing organic molecules. Among the diverse functional groups utilized for this purpose, N-substituted biheterocycles stand out for their wide range of biological activities, drawing considerable interest from medicinal chemists.9−16 Due to their extended functionalization, N-containing biheterocycles exhibit specific interactions with various biological targets such as receptors, enzymes, and even DNA, which makes them favorable for drug discovery. Moreover, their structural diversity allows researchers to design molecules with desired properties, including improved selectivity and reduced toxicity.17,18 Due to their diverse biological characteristics, quinoline and triazoles play an essential role in medicinal chemistry, and significant efforts have been made in the recent past to develop new functionalized quinoline-based triazole derivatives against cancer.19,20 The presence of N atoms in both the triazole and quinoline core systems enhances their basic character and makes them more specific toward target proteins through hydrogen bonding. Polarity is one of the crucial aspects of making an organic molecule clinically favorable while lowering its lipophilic nature, thus intensifying its solubility in an aqueous biological environment.21

The MCF-7 cell line is commonly employed as the cell line model in breast cancer studies. Because of its extensive past and ER expression, it is one of the most employed breast cancer cell lines.22,23 When it comes to HR/HER status (estrogen receptor + human epidermal growth factor receptor/progesterone receptor), most breast cancer patients (72.7%) are HR+/HER2–.24 Being one of the rare HR+/HER2– positive breast cancer cell lines, MCF-7 cells are extremely important models for researching invasive breast cancer.25 In the present work, a one-pot telescopic approach is demonstrated for the synthesis of quinoline-based triazole, which could be a potential pharmacophore against MCF-7 breast cancer.

Results and Discussion

Chemistry

Over the past few years, new synthetic methodologies and improved techniques have been a center of interest for the synthesis of task-specific heterocyclic molecules.26,27 Herein, a one-pot telescopic approach was developed for the synthesis of disubstituted 1,2,3-triazole derivatives (Figure 1). To carry out this transformation, earlier quinoline was functionalized by various substituted phenols 2a–j in the presence of K2CO3 in DMF at 100 °C for 2 h to furnish 3a–j. Further functionalization of intermediate compounds 3a–j without isolation was carried out with addition of cyanoacetamide (4) or ethyl cyanoacetate (5) in the presence of NaN3 and NH4Cl at 80 °C for 3 h to produce 6a–j with moderate to good yield. [Caution:Sodium azide (NaN3) produces hydrazoic acid (HN3) in acidic media. Hydrazoic acid is a volatile, explosive, and highly toxic compound. Reactions with these reagents should be undertaken with the proper safety precautions.]

Figure 1.

Figure 1

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One-pot telescopic synthesis of substituted quinoline-based triazole derivatives.

The proposed method is advantageous, as it can reduce the overall time of the reaction and can minimize the use of the solvent. To establish the formation of biheterocycle 6a, various characterization techniques were used. Compound 6a showed the −CH2 protons as a multiplet around 4.25 ppm, and −CH3 protons were observed at 1.25 ppm as a triplet, whereas an aromatic singlet proton was observed at 8.5 ppm, which was slightly shielded relative to its corresponding intermediate stage, and other aromatic protons appeared between 7 and 8 ppm. In 13C NMR spectrum, the carbonyl carbon appeared at 161 ppm, whereas −CH2 and −CH3 carbons appeared at 61 and 14 ppm, respectively. The IR spectrum of 6a showed carbonyl stretching around 1700 cm–1, with its molecular ion signal at m/z 361.1321 [M+H]+. Similarly, all the other products 6b–j were thoroughly analyzed by spectroscopic and analytical techniques.

In Silico Studies

DFT and Docking Study

The HOMO–LUMO energy gap and the MEP surface were calculated using optimum geometry according to the theory of B3LYP/6-311g*(d,p)28 for 6a–g and i) and B3LYP/dgdzvp29 for 6h and 6j to predict the active sites in the synthesized compounds (Table 1, Supporting Information). Compounds 6f (4.59 eV) and 6c (4.6 eV) exhibited a larger HOMO–LUMO energy gap; hence, they are the most structurally stable molecules among all. Furthermore, it is shown that the HOMO electron density is mostly located in the quinoline moiety, whereas the LUMO electron density spreads toward the triazole region. The MEP pictures show that the most negative regions (red) and positive regions (blue) spread throughout the quinazolinone system, indicating that the pi electrons are delocalized over the moiety, resulting in enhanced stability and more delocalization of electron density. VEGFR-2 was shown to be one of the major pathways involved in tumor angiogenesis. It has long been known that inhibiting the VEGFR-2 pathway could have the potential antiangiogenic and anticancer responses.30

Table 1. Cytotoxicity of 6a–j against Human Breast Cancer Cellsa.
Compoundsa MCF-7b
6a 90 ± 0.2
6b 53 ± 0.4
6c 62.5 ± 0.4
6d 65 ± 0.3
6e 19 ± 0.5
6f 10 ± 0.2
6g 12 ± 0.6
6h 17.5 ± 1.4
6i 42.5 ± 1.4
6j 20 ± 0.9
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a

IC50 values (μM) are the average ± SD of three individual experiments.

b

Breast cancer cells.

Docking for EGFR or Other RTKs

Docking experiments demonstrated that all the synthesized compounds can interact with the human VEGFR-2 kinase receptor and exhibit a consistent binding mechanism in the VEGFR-2 receptor’s binding pocket (PDB ID: 6GQO). The energetic and geometric conformations of all molecules in the binding sites were evaluated, and the best orientations for 6GQO were predicted according to a standard protocol.31 Docking scores for all of the compounds were achieved in the range of −8.9 to −8.2 kcal mol–1. Furthermore, it appears that there is a good correlation between the calculated binding affinity and the IC50 values, as given in Table 1. By comparison, 6f exhibited an exceptional ability to interact with VEGFR-2 kinase receptor by having remarkable hydrophobic interactions through GLU815, ASP1046, ARG1027, CYS1024, ASP814, and ILE888, with a binding energy of −8.9 kcal/mol. Thus, it was anticipated that the synthesized quinoline-based triazole derivatives may possess cytotoxic properties, possibly through the RTKs.

In Vitro Study

Cytotoxicity

An optimal antineoplastic drug should generally have low cytotoxicity toward noncancerous cells and specificity for destroying malignant cells.32 Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to quantitatively assess mitochondrial integrity is an efficient method of screening for the cellular proliferation index in a variety of cytotoxic ligands. The MTT assay can be used effectively to quantify the variance in cancer cell proliferation using the multiwall format with different intervals.33 In this study, the cytotoxicity of quinoline-based triazole derivatives was evaluated in MCF-7 breast cancer cells and compared against noncancerous human embryonic kidney cells (HEK-293). Among the 10 derivatives studied, 6f and 6g showed strong cytotoxicity, with excellent IC50 values against the human breast cancer cell line (Table 1) and with less toxicity against noncancerous cells after 24 h of treatment (Supporting Information).

Intercellular ROS Determination

Unusual ROS levels throughout various stages of cancer progression have contradictory effects on cell proliferation and death.34 Normal cell viability requires a physiological concentration of ROS that is kept in balance to maintain the basal cellular turnover. However, the subnormal ectopic ROS buildup encourages cell proliferation and subsequently causes the malignant transformation of normal noncancerous cells. High ROS concentrations damage chromosomes, lipid bilayers, proteins, and other cellular components, ultimately resulting in cell death. Therefore, despite their concentration-based complexities, scavenging abnormally increased ROS to prevent early neoplasia and maintaining basal, threshold levels of ROS for functional immune cell-intrinsic and -extrinsic pathways at the tumor microenvironment (TME) are necessary.35 Herein, the role of 6f and 6g in inducing ROS in MCF-7 cells was investigated using DCFDA dye. Upon cellular esterase-based deacetylation, the cell-permeable H2DCFDA diffuses into cells and form 2′,7′-dichlorodihydrofluorescein (H2DCF). H2DCF is quickly oxidized to 2′,7′-dichlorofluorescein (DCF), which is fluorescent at excitation and emission wavelengths of 498 and 522 nm, respectively, in the presence of ROS. As shown in Figure 2, the amount of ROS induction increased with the administration of 6f or 6g, which was compared with the standard cytotoxic drug cisplatin. This nuclear stain suggests that the generation of ROS was distributed in the cytoplasm and nucleus. To confirm this study, the quantity of ROS was measured using flow cytometry (Figure 3), where 50% of control cells showed basal generation of ROS. Treatment with 6f (10 μM) and 6g (12 μM) subsequently increased the cell population with ROS production, and 6f even showed a higher ROS generation than the positive control (5 μM), which confirms their cytotoxic potential through the generation of ROS.

Figure 2.

Figure 2

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Qualitative analysis of ROS in MCF-7 treated with 6f and 6g. Magnification, 20×; scale bar, 150 μm. The images are an overview of three different experiments.

Figure 3.

Figure 3

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(A) ROS generation in MCF-7 induced by compounds 6f and 6g and quantified by flow cytometry. (B) Bar diagram representing the percentage of ROS generation. The images are an overview of three independent investigations as mean ± SD. ***p < 0.001 vs control.

Apoptosis Induction and Mitochondrial Membrane Potential Loss

One of the key characteristics of cancer cells is their ability to undergo unchecked cell growth, eventually with emergence of treatment resistance.36 To study apoptotic cell death in MCF-7, we performed acridine orange (AO)/ethidium bromide (EtBr) staining. The basic principle behind the staining process is that when AO is incorporated into a double-stranded nucleic acid (DNA), it produces green fluorescence, and when it is coupled to a single-stranded nucleic acid such as RNA, it produces red fluorescence. When membrane integrity is compromised, EtBr intercalates into DNA to produce red fluorescence.37 This dual staining method shows four distinct colors with three stages of apoptosis. Early apoptotic cells have irregularly shaped green nuclei, but vivid green spots, pieces, or apoptotic bodies indicate chromatin condensation. Late-stage apoptotic cells associated with severely fragmented chromatin and orange-to-red nuclei resemble necrotic cells of uniformly ordered orange-to-red nuclei.38 As depicted in Figure 4, the control exhibited live cells with green fluorescence (white arrows).

Figure 4.

Figure 4

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Products 6f/g induced cell apoptosis observed using AO/EtBr staining indicative of live cells (L) [white arrows], early apoptotic (EA) [red arrows], late apoptotic (LA) [blue arrows], and necrosis (N) [yellow arrows]. The images are representative of three independent experiments.

Compound 6f (10 μM) showed an increase in the early apoptotic cells (red arrows) with a few late apoptotic cells (blue arrows). 6g (12 μM) exhibited a lesser number of death cells, with mostly necrotic (yellow arrows) and late apoptotic cells. The study was confirmed with cisplatin (5 μM), which showed an equal distribution of early, late, and necrotic cells. Previous studies have confirmed that death via necrosis may lead to a poor prognosis for cancer patients, which suggests the potential of 6f as an effective anticancer compound compared to 6g.39

It has been established that mitochondria serve as both the cell’s energy store and the prime location of ATP synthesis. Through modifications to the mitochondrial energy matrix, cancer cells can advantageously change their cellular energetics and metabolism. Mitochondria as cellular energy powerhouse are attractive candidates for anticancer drug development, which affects cell growth, division, tumor progression, and even the response toward medications. It is interesting to note that because histone protection and a repair mechanism are absent, mitochondrial DNA (mtDNA) is extremely susceptible to the effects of cancer drug treatment and may potentially be a useful target.40 It is commonly recognized that the early stages of the mitochondrion-mediated apoptosis pathway involve mitochondrial damage and the loss of the mitochondrial membrane potential (ΔΨm), which is regarded as a characteristic of apoptosis. By releasing cytochrome-c and activating caspases, cells with a reduced ΔΨm are primed for apoptosis.41

To study the mitochondrial membrane potential loss, Rhodamine-123, a cationic fluorescent dye, was used for the identification of actively respiring mitochondria. The dye diffuses across the inner membrane of the mitochondria due to negative membrane potential, and the dye will be lost along with potential, which could cause the fluorescence intensity to decrease. The flow cytometry data suggested (Figure 5), via the loss of MMP, that fluorescence intensity increases after treatment with 6f (10 μM) and 6g (12 μM). When compared to the basal control level of 8%, after treatment with 6f/6g there was a significant increase in fluorescence to 14% for 6g and even higher to 23% with 6f, thus clearly revealing the mitochondrial involvement in 6f/6g-induced apoptosis.

Figure 5.

Figure 5

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(A) 6f/6g-induced mitochondrial membrane potential loss (MMP) quantified by flow cytometry. (B) Bar diagram representing the percentage of MMP loss. The images represent three independent investigations as mean ± SD. ***p < 0.001 vs control.

Consequently, the elevated mRNA levels of pro-apoptotic genes Bax and Bad and the decreased level of expression of antiapoptotic gene Bcl-2 (Figure 6) indicate the intrinsic mitochondrial pathway while inducing apoptosis.

Figure 6.

Figure 6

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Effect of 6f/6g on pro- and antiapoptotic gene expression. (a, b) Expression of proapoptotic genes. (c) Expression of antiapoptotic genes. Data represent three independent studies as mean ± SD. ***p < 0.001 vs control; **p < 0.05 vs control.

Nuclear Morphology Analysis

Studies on the influence of 6f and 6g on the nuclear morphology of MCF-7 cells were carried out using DAPI staining to further corroborate and visually confirm the induced apoptotic death. The control cells showed healthy nuclear morphology with the proper shape of the nucleus, whereas the administration of 6f (10 μM) and 6g (12 μM) increased condensed and subsequently fragmented nuclei (white arrows in Figure 7), similar to cisplatin (5 μM).

Figure 7.

Figure 7

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6f/6g-induced DNA fragmentation in the MCF-7 cells. The ligand-induced DNA fragmentation indicated by the white arrow was observed using DAPI staining. Images represent three individual experiments. Scale bar, 150 μm.

Intercellular Localization of 6f and 6g

Confocal fluorescence microscopy was used to visualize the intercellular localization of both 6f and 6g by comparison with the control cisplatin. The MCF-7 cells were treated with 6f/6g and cisplatin for 24 h to facilitate intercellular localization.

Control cells showed fluorescence in the DAPI filter with an emission at 461 nm, confirming the intact healthy nucleus, and the second filter emission at 583 nm did not show any fluorescence and appeared black, which eliminates the possible background noise. 6f showed a strong red fluorescence along with DAPI, confirming the presence of 6f inside the cytoplasm or nucleus (Figure 8). However, the fluorescence that was eliminated by 6g was competitively low. This preliminary study confirmed the drug specificity of 6f toward mitochondria, which in turn induces apoptosis via an intrinsic pathway inside MCF-7 cancer cells.

Figure 8.

Figure 8

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Intercellular localization of 6f/6g in MCF-7 cells after 24 h of treatment, visualized by confocal fluorescence microscopy. From left, bright field, drug visualization in REF filter, DAPI, and merged images. Scale bar, 150 μm.

Conclusion

A one pot-telescopic approach has been demonstrated for the synthesis of quinoline-based triazole derivatives 6a–j, which is a powerful and effective methodology for the sustainable synthesis of organic molecules. Compound 6f imparted the best docking score (−8.9 kcal mol–1) against the kinase receptor VEGFR-2. Moreover, DFT analysis showed the structural stability of the synthesized compounds. The synthesized compounds showed potential antitumor activity against the human breast cancer cell line (MCF-7). Among the synthesized compounds, 6f and 6g exhibit a better and broad spectrum of antitumor activity along with an active oxidative stress induction. The presence of 6f in the cytoplasm along with the increase in ROS production and reduction in MMP clearly showed the ability to target mitochondria by 6f. A future study needs to be performed to confirm this hypothesis by tracking mitochondria as a potential target for 6f.

Acknowledgments

The authors are grateful to VIT-SEEDGRANT for the financial support and to VIT-SIF for all the facilities. J.M. is thankful to VIT-Vellore for the TRA-ship.

Glossary

Abbreviations

TNBC

triple-negative breast cancer

ER

estrogen receptor

RTK

tyrosine kinase

EGFR

epithelial growth factor receptor

PDGFR

platelet-derived growth factor receptor

FGFR

fibroblast growth factor receptor

VEGFR

vascular endothelial growth factor receptor

MEP

molecular electrostatic potential

MMP

mitochondrial membrane potential loss

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00289.

  • Experimental details and characterization (PDF)

The authors declare no competing financial interest.

Supplementary Material

ml4c00289_si_001.pdf (3.8MB, pdf)

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