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Abstract

A series of novel naphthoquinone-fused podophyllotoxins containing fluoro and trifluoromethyl substituents were synthesized in a medium with good yields using two different synthetic approaches: microwave-assisted four-component reactions of 2-hydroxy-1,4-naphthoquinone, tetronic acid, fluorinated arylaldehydes, and ammonium acetate, and microwave-assisted three-component reactions of 2-amino-1,4-naphthoquinone, tetronic acid, and fluorinated arylaldehydes. The structures of all products were confirmed by spectral analysis. Together, cytotoxicity assessment of the products against four human cancer cell lines (human carcinoma [KB], human hepatocellular carcinoma [HepG2], lung cancer [A549], breast carcinoma [MCF7], and human embryonic kidney [Hek-293]) was performed by MTT assay. Among the obtained compounds, compound 7f turned out to be the most potent anticancer agent with significant cytotoxic activity against KB, HepG2, and MCF cancer cell lines.

Keywords

fluorinated compounds 4-azapodophyllotoxin naphthoquinone cytotoxic activity microwave-assisted reaction four-component reaction

Introduction

Fluorine, the small and highly electronegative element, is a critical element for the design of biologically active compounds. The incorporation of at least one fluorine atom or a trifluoromethyl group into bioactive compounds could improve metabolic stability, membrane permeability, bioavailability, and the binding affinity of the compound to a target protein,¹ which results in profound pharmacological activities.^2–8 In recent years, fluorinated compounds have been used for a broad range of therapeutic purposes,⁹ such as anti-cancer agents,¹⁰ antimicrobial agents, anti-inflammatory agents,¹¹ anesthetics, and central nervous system drugs.¹² For example, celecoxib (1), a selective cyclooxygenase-2 inhibitor, has been known as a nonsteroidal anti-inflammatory drug for the treatment of rheumatoid arthritis and osteoarthritis (Figure 1).¹³ Fluoroquinolones, such as ciprofloxacin, norfloxacin, levofloxacin, trovafloxacin, and lascufloxacin (2) (Figure 1), are potent antibacterial agents possessing improved oral absorption and systemic distribution.¹ Inspired by the important role of fluorinated molecules in drug discovery and development, many efforts have been made to attach the fluorine atom to a variety of bioactive molecules.^14–16

Figure 1.

Some fluoro-pharmaceuticals and potent 4-azapodophyllotoxin compounds.

On the other hand, podophyllotoxin (Figure 1), a tubulin polymerization inhibitor, has been known as an antitumor agent.¹⁷ 4-Azapodophyllotoxins (3), podophyllotoxin derivatives with a nitrogen atom at position C-2 of the podophyllotoxin skeleton, possess pronounced biological activities, for example, inhibition of cancer cell growth,¹⁸ induction of cell cycle arrest in the G2/M phase and apoptosis,^19,20 tubulin polymerization inhibition,²⁰ and vascular disrupting activity.²¹ In our previous studies, several 4-azapodophyllotoxin derivatives were synthesized and evaluated against five different cancer cell lines.^22–24 Among the synthesized derivatives, 11-aryl-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1,5,10(3H)-trione 4 turned out to be a potent cytotoxic derivative against HepG2 and SK-Lu-1 cell lines (Figure 1). Due to the outstanding biological activities of 4-azapophyllotoxins and fluorine-containing compounds, and our interest in the discovery of bioactive compounds,^25–30 herein, we have focused our research interest toward the introduction of the fluorine atom to ring E of 11-aryl-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1,5,10(3H)-trione derivatives (4), together with their cytotoxic evaluation against four human cancer cell lines (KB, HepG2, MCF7, A459).

Results and Discussion

The different pathways for the synthesis of a series of fluorinated podophyllotoxin-naphthoquinone compounds (10) are outlined in Figure 2. In the first pathway, microwave-assisted four-component reactions of 2-hydroxy-naphthoquinone, tetronic acid, fluorinated arylaldehydes and ammonium acetate were performed in glacial acetic acid (gl. AcOH) at 120 °C. After completion of the reactions, the products 10a-g were obtained in low to medium yields (Table 1). Whereas, in the second pathway, microwave-assisted three-component reactions of 2-amino-naphthoquinone, tetronic acid, and fluorinated arylaldehydes were conducted in gl. AcOH as a solvent and p-TsOH 20 mol% as a catalyst at 120 °C in 15 min to afford products 10a-g in good yields (68-82%). It was observed that the three-component synthetic approach was offering higher yields in comparison with the four-component synthetic approach. Moreover, the three-component synthetic approach appeared to be a more efficient way to form fluorinated podophyllotoxin-naphthoquinones with bulky substituents.

Figure 2.

The different synthetic pathways for the synthesis of products 10a-g.

Figure 3.

Chemical structure of product 10a.

Table 1.

Microwave-Assisted Synthesis of Products 10a-g.

Product	Ar	Time (min)	Yield (%)
Product	Ar	Time (min)	First pathway	Second pathway
10a	2-F-4-MeOC₆H₃	20	39	71
10b	3-F-4-MeOC₆H₃	20	42	74
10c	2,6-F₂-4-MeOC₆H₂	25	37	70
10d	2-CF₃-4-MeOC₆H₃	20	36	73
10e	2-F-4-OHC₆H₃	20	17	72
10f	4-(4-fluorophenoxy)C₆H₄	25	Trace	69
10g	4-CF₃OC₆H₄	20	69	78

The structures of all synthesized compounds 10a-g were fully characterized by IR, ¹H and ¹³C NMR, and HRESIMS. The ¹H and ¹³C assignments of products 10a-g were based on the NMR data of the podophyllotoxin-naphthoquinones 4, reported in the previous study.²³ For example, the ¹H NMR spectrum of product 10a represented a singlet at δ_H 10.61 ppm for the –NH group. The signals of 4 aromatic protons in the naphthoquinone ring appeared at δ_H 8.05 (1H, dd, J = 1.2, 7.2 Hz, H-6), 7.87 (1H, dd, J = 1.2, 7.2 Hz, H-9), and 7.85-7.78 (2H, m, H-8, H-7). Meanwhile, one triplet at δ_H 7.20 (1H, t, J = 8.4 Hz), two doublets of doublets at δ_H 6.70 (1H, dd, J = 2.4, 12 Hz) and 6.65 (1H, dd, J = 2.4, 8.4 Hz), and one singlet at δ_H 3.70 (3H, s) were referred to protons in the 2-fluoro-4-methoxyphenyl group. The singlet at δ_H 5.18 was attributed to the H-11 proton, two doublets at δ_H 4.94 and δ_H 4.90 with a coupling constant of 16.8 Hz were identified as the 3-CH₂ protons in the γ-butyrolactone ring. In the ¹³C NMR spectrum, 22 carbon resonances were observed.

In the next part of this work, the synthetic derivatives 10a-g were subjected to evaluation of their cytotoxicity against four cancer cell lines (KB, HepG2, A549, and MCF7 cells). It was observed that almost the products displayed high inhibitory activity against the 4 cancer cell lines. The products exhibited the highest cytotoxic activity against the KB cancer cell line with IC₅₀ values ranging from 0.6 μM to 2.54 μM. As shown in Table 2, the cytotoxic activity of products 10f (IC₅₀ = 0.6 ± 0.01 μM) and 10g (IC₅₀ = 1.11 ± 0.01 μM) was better than that of the positive control ellipticine (IC₅₀ = 1.53 ± 0.01 μM) against KB cells. Moreover, these products also exhibited higher cytotoxicity to HepG2 cells with IC₅₀ values ranging from 1.05 to 1.11 μM, compared to that of ellipticine. In the case of A549 cells, the cytotoxic activity of products 10b (IC₅₀ = 1.13 ± 0.07 μM) and 10g (IC₅₀ = 1.39 ± 0.10 μM) were greater than that of ellipticine (IC₅₀ = 1.58 ± 0.03 μM). Meanwhile, products 10c,d exhibited moderate cytotoxic effect against all four cancer cell lines with IC₅₀ > 5.00 μM. Compounds 10a-g were also evaluated for their cytotoxicity to a human embryonic kidney (Hek-293) cell line. Products 10a,c,d displayed the lowest toxicity to Hek-293 with IC₅₀ > 20 μM. Compounds 10e and 10g exhibited cytotoxicity against the Hek-293 cell line with IC₅₀ values of 1.54 ± 0.14 and 1.08 ± 0.01 µM, respectively. Product 10f showed lower toxicity to Hek-293, with an IC₅₀ value of 3.68 ± 0.02 µM. Taken together, the cytotoxic evaluation revealed that compound 10f (Ar = 4-(4-fluorophenoxy)phenyl) was a highly potent cytotoxic agent against cancer cell lines.

Table 2.

Cytotoxicity of Products 10a-g.

Product	IC₅₀, µM
Product	KB	HepG2	A549	MCF7	Hek-293
10a	2.54 ± 0.01	3.13 ± 0.01	4.42 ± 0.01	2.65 ± 0.01	21.87 ± 0.01
10b	2.36 ± 0.01	3.24 ± 0.01	1.13 ± 0.07	3.43 ± 0.03	10.04 ± 0.10
10c	> 5.00	> 5.00	> 5.00	> 5.00	40.06 ± 0.21
10d	> 5.00	> 5.00	> 5.00	> 5.00	21.91 ± 0.26
10e	1.86 ± 0.03	> 5.00	1.82 ± 0.01	2.69 ± 0.03	1.54 ± 0.14
10f	0.60 ± 0.01	1.05 ± 0.03	> 5.00	2.12 ± 0.04	3.68 ± 0.02
10g	1.11 ± 0.01	1.11 ± 0.03	1.39 ± 0.10	2.59 ± 0.03	1.08 ± 0.01
Ellipticine	1.53 ± 0.04	1.50 ± 0.03	1.58 ± 0.03	1.83 ± 0.07	6.33 ± 0.04

Materials and Methods

Experimental procedures for the synthesis of products 10a-g and the MTT assay protocol are provided in the supporting information.

11-(2-Fluoro-4-Methoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]Quinolin-1,5,10(3H)-Trione (10a)

Yield 152 mg (39%—first pathway), 279 mg (71%—second pathway), orange solid, mp. 260 °C. IR (KBr) ν_max/cm⁻¹ 3356, 3168, 3068, 2960, 2837, 1741, 1671, 1657, 1623, 1589, 1495, 1396, 1336, 1299, 1238, 1196, 1151, 1100, 1028, 1008, 950, 930, 826, 790, 722. ¹H NMR (DMSO-d₆, 600 MHz): δ 10.61 (1H, s, –NH), 8.05 (1H, dd, J = 1.2, 7.2 Hz, H-6), 7.87 (1H, dd, J = 1.2, 7.2 Hz, H-9), 7.85-7.78 (2H, m, H-8, H-7), 7.20 (1H, t, J = 8.4 Hz), 6.70 (1H, dd, J = 2.4, 12.0 Hz), 6.65 (1H, dd, J = 2.4, 8.4 Hz), 5.18 (1H, s, H-11), 4.94 (1H, d, J = 16.8 Hz, H-3a), 4.90 (1H, d, J = 16.8 Hz, H-3b), 3.70 (3H, s, OCH₃). ¹³C NMR (DMSO-d₆, 150 MHz) δ 181.9 (C-10), 179.5 (C-5), 170.8 (C-1), 159.7 (1C, d, J = 245 Hz, C-2'), 159.3 (1C, d, J = 11.25 Hz, C-4'), 155.9 (C-3a), 139.5 (C-4a), 134.9, 133.3, 131.8, 131.1 (1C, d, J = 5.0 Hz), 130.1, 125.9, 125.7, 123.8 (1C, d, J = 15.0 Hz), 117.9, 110.4, 101.2, 100.9 (1C, d, J = 26.3 Hz), 66.0 (C-3), 55.4 (OCH₃), 28.2 (C-11). HRESIMS: Found m/z 392.0938 [M + H]⁺_, calcd. for [C₂₂H₁₅FNO₅]⁺: 392.0929.

11-(3-Fluoro-4-Methoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]Quinolin-1,5,10(3H)-Trione (10b)

Yield 164 mg (42%—first pathway), 290 mg (74%—second pathway), orange solid, mp. 278 °C. IR (KBr) ν_max/cm⁻¹ 3348, 3196, 3067, 2969, 2938, 2876, 2840, 1742, 1664, 1633, 1591, 1491, 1396, 1337, 1304, 1287, 1272, 1236, 1193, 1135, 1115, 1068, 1027, 1007, 954, 779, 758, 725, 679. ¹H NMR (DMSO-d₆, 600 MHz): δ 8.06 (1H, dd, J = 1.2, 7.8 Hz), 7.90 (1H, dd, J = 1.2, 7.8 Hz), 7.84 (1H, td, J = 1.2, 7.2 Hz), 7.81 (1H, td, J = 1.2, 7.2 Hz), 7.15 (1H, dd, J = 1.8, 12.0 Hz), 7.09 (1H, dd, J = 1.8, 8.4 Hz), 7.04 (1H, t, J = 8.4 Hz), 4.99 (1H, d, J = 16.2 Hz), 4.97 (1H, s), 4.90 (1H, dd, J = 1.2, 16.2 Hz), 3.77 (3H, s). ¹³C NMR (DMSO-d₆, 150 MHz) δ 182.2, 179.5, 171.2, 155.9, 151.3 (1C, d, J = 244.5 Hz), 145.9 (1C, d, J = 10.5 Hz), 139.4, 137.5 (1C, d, J = 6.0 Hz), 134.9, 133.4, 131.9, 130.3, 126.0, 125.8, 124.2 (1C, d, J = 3.0 Hz), 117.9, 115.6 (1C, d, J = 18.0 Hz), 113.6, 101.7, 66.1, 56.0, 34.2. HRESIMS: Found m/z 392.0945 [M + H]⁺_, calcd. for [C₂₂H₁₅FNO₅]⁺: 392.0929.

11-(2,6-difluoro-4-methoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1,5,10(3H)-trione (10c)

Yield 151 mg (37%—first pathway), 287 mg (70%—second pathway), orange solid, mp. 272 °C. IR (KBr) ν_max/cm⁻¹ 3367, 3065, 2963, 2844, 1740, 1672, 1635, 1588, 1496, 1441, 1397, 1336, 1299, 1197, 1140, 1066, 1021, 1006, 953, 930, 833, 790, 721, 580, 537. ¹H NMR (DMSO-d₆, 600 MHz): δ 10.69 (1H, s), 8.05 (1H, dd, J = 1.2, 7.8 Hz), 7.89 (1H, dd, J = 1.2, 7.8 Hz), 7.84 (1H, td, J = 1.2, 7.2 Hz), 7.81 (1H, td, J = 1.2, 7.2 Hz), 6.62 (2H, d, J = 10.8 Hz), 5.33 (1H, s), 4.94 (1H, d, J = 16.2 Hz), 4.90 (1H, dd, J = 0.6, 16.2 Hz), 3.73 (3H, s). ¹³C NMR (DMSO-d₆, 150MHz) δ 181.8, 179.4, 170.8, 161.0 (2C, d, J = 245 Hz), 159.6, 156.7, 139.8, 135.1, 133.4, 131.6, 129.9, 126.0, 125.7, 116.7, 111.3, 99.4, 98.1 (2C, d, J = 28.75 Hz), 66.0, 55.9, 24.4. HRESIMS: Found m/z 410.0853 [M + H]⁺_, calcd. for [C₂₂H₁₄F₂NO₅]⁺: 410.0835.

11-(4-methoxy-2-(trifluoromethyl)phenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1,5,10(3H)-trione (10d)

Yield 159 mg (36%—first pathway), 322 mg (73%—second pathway), orange solid, mp. 282 °C. IR (KBr) ν_max/cm⁻¹ 3067, 2953, 2841, 2263, 2131, 1749, 1669, 1591, 1497, 1396, 1299, 1241, 1196, 1155, 1115, 1026, 1004, 930, 889, 825, 721, 663, 587. ¹H NMR (DMSO-d₆, 600 MHz): δ 10.63 (1H, s), 8.07–8.05 (1H, m), 7.86–7.79 (3H, m), 7.41 (1H, d, J = 8.4 Hz), 7.09–7.06 (2H, m), 5.37 (1H, s), 4.92 (1H, d, J = 16.2 Hz), 4.87 (1H, d, J = 16.2 Hz), 3.76 (3H, s). ¹³C NMR (DMSO-d₆, 150 MHz) δ 181.8, 179.6, 170.3, 157.56, 155.6, 139.5, 136.1, 134.9, 133.3, 133.0, 131.8, 130.1, 127.5, 126.3 (1C, d, J = 248 Hz, CF₃), 125.9, 125.8, 118.8, 118.1, 111.0, 101.8, 65.7, 55.4, 31.0. HRESIMS: Found m/z 442.0886 [M + H]⁺_, calcd. for [C₂₃H₁₅F₃NO₅]⁺: 442.0897.

11-(2-fluoro-4-hydroxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1,5,10(3H)-trione (10e)

Yield 64 mg (17%—first pathway), 272 mg (72%—second pathway), orange solid, mp. 220 °C. IR (KBr) ν_max/cm⁻¹ 33272, 3127, 3045, 2955, 2925, 1729, 1665, 1619, 1594, 1496, 1400, 1332, 1297, 1196, 1154, 1074, 1015, 1001, 964, 932, 879, 787, 718, 672, 583, 541. ¹H NMR (DMSO-d₆, 600 MHz): δ 10.57 (1H, s), 9.76 (1H, s), 8.04 (1H, dd, J = 1.2, 7.8 Hz), 7.86 (1H, dd, J = 1.2, 7.8 Hz), 7.81 (1H, td, J = 1.2, 7.2 Hz), 7.78 (1H, td, J = 1.2, 7.2 Hz), 7.06 (1H, t, J = 8.4 Hz), 6.48 (1H, dd, J = 2.4, 8.4 Hz), 6.43 (1H, dd, J = 2.4, 12.0 Hz), 5.10 (1H, s), 4.92 (1H, d, J = 16.8 Hz), 4.86 (1H, d, J = 16.8 Hz). ¹³C NMR (DMSO-d₆, 125 MHz) δ 182.0, 179.7, 171.0, 159.8 (1C, d, J = 245 Hz), 157.7 (1C, d, J = 12.5 Hz), 155.9, 139.4, 135.0, 133.4, 131.9, 131.2 (1C, d, J = 6.25 Hz), 130.1, 126.0, 125.8, 122.4 (1C, d, J = 13.75 Hz), 118.2, 111.6, 102.1 (1C, d, J = 25 Hz), 101.4, 66.1, 28.2. HRESIMS: Found m/z 378.0791 [M + H]⁺_, calcd. for [C₂₁H₁₃FNO₅]⁺: 378.0773.

11-(4-(4-fluorophenoxy)phenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1,5,10(3H)-trione (10f)

Yield 313 mg (69%—second pathway), orange solid, mp. 275 °C. IR (KBr) ν_max/cm⁻¹ 3304, 3070, 3036, 2934, 1751, 1722, 1666, 1596, 1493, 1395, 1332, 1298, 1247, 1212, 1026, 1004, 927, 863, 831, 802, 757, 719, 595, 520, 496. ¹H NMR (DMSO-d₆, 600 MHz): δ 10.62 (1H, s), 8.05 (1H, dd, J = 1.2, 7.2 Hz), 7.90 (1H, dd, J = 1.2, 7.2 Hz), 7.84 (1H, td, J = 1.2, 7.2 Hz), 7.80 (1H, td, J = 1.2, 7.2 Hz), 7.33–7.30 (2H, m), 7.20–7.16 (2H, m), 7.03–7.00 (2H, m), 6.87–6.84 (2H, m), 4.99 (1H, s), 4.98 (1H, d, J = 16.8 Hz), 4.89 (1H, dd, J = 0.6, 16.8 Hz). ¹³C NMR (DMSO-d₆, 150 MHz) δ 182.1, 179.5, 171.1, 158.2 (1C, d, J = 237.5 Hz), 155.9 (2C), 152.3 (1C, d, J = 2.5 Hz), 139.4, 139.3, 134.9, 133.4, 131.8, 130.2, 129.6 (2C), 126.0, 125.7, 120.8 (2C, d, J = 8.8 Hz), 118.3, 117.6 (2C), 116.5 (2C, d, J = 23.8 Hz), 102.0, 66.1, 34.2.

11-(4-(trifluoromethoxy)phenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1,5,10(3H)-trione (10g)

Yield 295 mg (69%—first pathway), 333 mg (78%—second pathway), orange solid, mp. 222 °C. IR (KBr) ν_max/cm⁻¹ 3427, 3119, 3072, 3042, 2960, 2883, 1754, 1667, 1634, 1595, 1497, 1396, 1334, 1301, 1253, 1220, 1191, 1132, 1052, 1026, 1002, 932, 822, 790, 723, 679, 628, 592, 572. ¹H NMR (DMSO-d₆, 600 MHz): δ 10.68 (1H, s), 8.06 (1H, dd, J = 1.8, 7.2 Hz), 7.88 (1H, dd, J = 1.8, 7.2 Hz), 7.83 (1H, td, J = 1.8, 7.2 Hz), 7.80 (1H, td, J = 1.8, 7.2 Hz), 7.48–7.45 (2H, m), 7.25 (2H, d, J = 8.4 Hz), 5.06 (1H, s), 4.98 (1H, d, J = 16.8 Hz), 4.90 (1H, dd, J = 0.6, 16.8 Hz). ¹³C NMR (DMSO-d₆, 150 MHz) δ 182.1, 179.4, 171.1, 156.1, 147.0, 143.6, 139.7, 134.9, 133.4, 131.8, 130.3, 129.9 (2C), 126.0, 125.8, 120.0 (1C, d, J = 255.0 Hz, CF₃), 120.7 (2C), 117.7, 101.6, 66.2, 34.6. HRESIMS: Found m/z 428.0767 [M + H]⁺_, calcd. for [C₂₂H₁₃F₃NO₅]⁺: 428.0741.

The NMR and HRESIMS spectra for the products 10a-g were shown in Supplemental Figures S1-S20.

Conclusions

Two different synthetic approaches were used in this study for the synthesis of novel fluorinated podophyllotoxin-naphthoquinone compounds. It turned out that, among these two methods, the most efficient was that using microwave-assisted three-component reactions of 2-amino-1,4-naphthoquinone, fluorinated arylaldehydes, and tetronic acid. All products were obtained in good yields and evaluated for their cytotoxic activities against KB, HepG2, A549, MCF7, and Hek-293 cell lines. Products 10a-g exhibited an inhibitory effect on the four cancer cell lines tested. Although compound 10g showed significant cytotoxic activity against all four cancer cell lines, this compound was also toxic to Hek-293 cells. Accordingly, owing to its potent cytotoxicity against KB, HepG2, and MCF7 cancer cell lines and low toxicity to Hek-293 cells, product 10f has been elected as the target compound for future research and development as an anticancer agent.

Supplemental Material

sj-doc-1-npx-10.1177_1934578X221133196 - Supplemental material for Synthesis and Cytotoxic Evaluation of Fluoro and Trifluoromethyl Substituents Containing Novel Naphthoquinone-Fused Podophyllotoxins

Supplemental material, sj-doc-1-npx-10.1177_1934578X221133196 for Synthesis and Cytotoxic Evaluation of Fluoro and Trifluoromethyl Substituents Containing Novel Naphthoquinone-Fused Podophyllotoxins by Nguyen Ha Thanh, Hoang Thi Phuong, Le Thi Tu Anh and Le Nhat Thuy Giang, Nguyen Thi Quynh Giang, Nguyen Tuan Anh, Dang Thi Tuyet Anh, Phan Van Kiem in Natural Product Communications

Footnotes

Acknowledgements

The authors are indebted to the Vietnam Academy of Science and Technology (code: CT0000.03/22-23) for financial support.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Our institution does not require ethical approval for reporting individual cases or case series.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article. This work was supported by the Vietnam Academy of Science and Technology (grant number CT0000.03/22-23).

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

ORCID iD

Phan Van Kiem

Supplemental Material

Supplemental material for this article is available online.

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