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Abstract

Objective: The study was conducted to evaluate the in vitro and in silico anticancer activity of fluorinated podophyllotoxin derivatives. Methods: Microwave-assisted multicomponent reactions were carried out in an Anton Paar Microwave Synthetic Reactor Monowave 400 in order to synthesize fluorinated podophyllotoxin derivatives. These products were identified by spectral analysis and evaluated for their cytotoxicity against 4 types of human cancer cell lines (KB, HepG2, A549, and MCF7), as well as human embryonic kidney (Hek) 293 cells using MTT protocol. Molecular docking was conducted using 2 crystal structures of tubulin—colchicine (PDB ID: 4O2B) and topoisomerase II—etoposide (PDB ID: 3QX3) complexes. Results: Two potent cytotoxic fluorinated podophyllotoxin–naphthoquinone compounds were synthesized in good yields. They displayed high cytotoxic activity against all the tested cell lines, with IC₅₀ values ranging from 0.58 to 3.17 µM. Notably, product 8a showed low toxicity against the Hek-293 cell line. Molecular docking results showed that products 8a and 8b participated in the same key interactions provided by etoposide with both topoisomerase and DNA chain domains. The binding energy values calculated for 8a and 8b are acceptable. Conclusion: This study revealed that products 8a and 8b exhibited promising in vitro and in silico anticancer activity and could be recognized as promising anticancer agents.

Keywords

fluorinated compounds naphthoquinone 4-aza-podophyllotoxin cytotoxic activity molecular docking

Introduction

Cancer, a serious disease in which abnormal cells grow uncontrollably, spreads to other parts of the body, and kills normal cells, has been known as the second leading cause of death after cardiovascular disease in the world. Thus, considerable attention has been paid to the discovery of potential anticancer agents, such as podophyllotoxin derivatives.^1-4 Although podophyllotoxins are good tubulin polymerization inhibitors, with antitumor activities, they mostly failed in clinical studies and caused many side effects.⁵ Semisynthetic derivatives of podophyllotoxin, such as etoposide (1) and teniposide, which are widely used as therapeutic agents in the treatment of cancers and venereal warts, exhibited reduced side effects in comparison to podophyllotoxin.^5-7 Thus, in order to discover new anticancer agents with fewer side effects, great interest has been devoted to 4-aza-podophyllotoxins,^8-14 which have shown a broad range of biological activities, such as vascular disruption effect,¹⁵ apoptosis-inducing effect,¹⁶ cell cycle arrest in the G2/M phase,¹⁶ inhibition of tubulin polymerization,¹⁷ and cancer cell growth inhibition.¹⁸ On the other hand, fluorine, the most electronegative element, has played an essential role in the design of pharmaceutically active molecules.^19-22 The attachment of at least one fluorine atom to biologically active compounds could improve bioavailability, membrane permeability, metabolic stability, and binding affinity, leading to significant pharmacological activities.^20,23-26 For example, Roche et al have reported a convenient route to rapidly construct a series of 50 aza-podophyllotoxin analogs using multicomponent reactions.¹⁸ Among 50 analogs, lead compound 2, with a difluoromethyl ether group on the B ring, has exhibited high selectivity against the human THP-1 leukemia cell line (IC₅₀ = 9 nM), pancreas cancer PSN-1 cell line (IC₅₀ = 24 nM), and a minimal toxicity to the nonmalignant kidney HEK293 cell line (IC₅₀ > 100 µM) (Figure 1). A 4-aza-podophyllotoxin derivative (3) with a fluorine atom on the E ring has caused cell cycle arrest at the G2/M phase and caspase-3 dependent apoptotic cell death and inhibition of tubulin polymerization in a lung (A549) cancer cell line (Figure 1).¹⁶

Figure 1.

Some potent podophyllotoxin derivatives.

A series of novel podophyllotoxin–naphthoquinones has been prepared and evaluated for their anticancer activity against 5 cancer cell lines.^9-11,27 4-Azapodophyllotoxin analogs (4) displayed outstanding cytotoxic activity against HepG2 and SK-Lu-1 cell lines with an IC₅₀ < 44 nM (Figure 1). Inspired by the profound biological activities of 4-aza-podophyllotoxin, especially 4-aza-podophyllotoxin containing either a difluoromethyl ether group (2) or one fluorine atom (3), as well as a continuation of our research on the discovery of bioactive compounds^28-34; herein, we introduce the synthesis of 2 new potent fluorinated podophyllotoxin–naphthoquinones via multicomponent reactions, and their cytotoxic evaluation against 4 human cancer cell lines (KB, HepG2, MCF7, and A459). Moreover, molecular docking studies were conducted to investigate more deeply and objectively the approximate binding modes of the 2 synthesized compounds.

Results and Discussion

In our previous study, we found that 3-component reactions of 2-amino-naphthoquinone, fluorinated aromatic aldehydes, and tetronic acid using p-toluenesulfonic acid (p-TsOH) as an acid catalyst and gl. AcOH as a solvent under microwave irradiation furnished fluorinated podophyllotoxin derivatives in high yield.²⁷ Accordingly, in this study, the synthesis of 2 new potent 4-azapodophyllotoxin containing fluorine atoms was conducted under the same optimized reaction conditions (outlined in Scheme 1). Upon completion of the reactions (20 min), 11-(3-fluoro-4-hydroxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinoline-1,5,10(3H)-trione (8a), and 11-(4-(difluoromethoxy)-3-hydroxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinoline-1,5,10(3H)-trione (8b) were obtained in good yields (73% and 68%, respectively). The structures of the obtained products 8a and 8b were completely elucidated by IR, HRESIMS, and ¹H and ¹³C NMR spectra.

Scheme 1.

Synthesis of fluorinated podophyllotoxin–naphthoquinone derivatives 8 under microwave irradiation.

The cytotoxic activities of the 2 products 8a and 8b against epidermoid carcinoma (KB), hepatoma carcinoma (HepG2), non-small lung (A549), and breast (MCF7) cancer cell lines were determined using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Ellipticine,^35,36 a powerful anticancer agent, was used as a positive control. As described in Table 1, products 8a and 8b exhibited a significant cytotoxic effect on all tested cancer cell lines with half maximal inhibitory concentrations (IC₅₀) ranging from 0.58 to 3.17 µM. These products displayed basically stronger cytotoxicity against KB, A549, and MCF7 cell lines than ellipticine. Especially, product 8a showed highly potent inhibitory activity with an IC₅₀ = 0.58-0.63 µM against KB, A549, and MCF7 cells, and low toxicity for the noncancerous Hek-293 cell line, with an IC₅₀ value of 22.87 µM. Thus, product 8a was a highly potent and selective anticancer agent.

Table 1.

Cytotoxicity of 8a and 8b Against KB, HepG2, A549, MCF7, and Hek-293 Cell Lines.

Product	IC₅₀, µM
Product	KB	HepG2	A549	MCF7	Hek-293
8a	0.63 ± 0.01	3.17 ± 0.04	0.67 ± 0.02	0.58 ± 0.02	22.87 ± 0.10
8b	0.61 ± 0.02	0.84 ± 0.01	1.04 ± 0.03	0.69 ± 0.01	3.15 ± 0.05
Ellipticine	1.53 ± 0.04	1.50 ± 0.03	1.58 ± 0.03	1.83 ± 0.07	6.33 ± 0.04

On the grounds of biological evaluation, it is of interest studying the interactions between products against potential anticancer dual targets, such as tubulin and topoisomerase. In this study, as a standard protocol, colchicine and etoposide (1) were redocked to validate the docking method before applying it to the investigated synthesized compounds. The result, shown in Figure 2, suggests the accuracy of our docking protocol due to the low RMSD values (<1.0 Å) and conserved key interactions. Colchicine, being a native ligand of tubulin, is located on the interface between the α and β subunits. It can prevent curved tubulin from adopting straight structures and thus inhibits microtubule assembly.^37,38 The methoxytropone ring of colchicine forms a hydrogen bond with Val181 of the α subunit. Besides, hydrophobic interactions were also created between colchicine and residues Ala180 α, Met259 β, and Cys241 β. The results are similar to those previously reported.^11,39

Figure 2.

Redocked poses (green) compared to original poses (yellow) of (A) colchicine in tubulin and (B) etoposide (1) in topoisomerase.

After validating the docking protocol for each target, 8a and 8b were docked into the active site of tubulin. The results for binding energy and interactions are summarized in Table 2. Compounds 8a and 8b were accommodated well in the colchicine binding pocket and formed the key interactions, like the co-crystal ligand. The main interactions included hydrogen bonding between the carbonyl group of the quinone ring and Val181α residue and multiple hydrophobic interactions of the pi-alkyl, alkyl-alkyl, and Van de Waals type with Ala180α, Met259β, Cys241β, and so on (Table 2, Figure 3). In addition, the binding energy of 8a and 8b were −17.73 and −16.50 kJ/mol, suggesting a lower binding affinity compared to colchicine.

Figure 3.

Interactions between compounds 8a and 8b with active site of tubulin.

Table 2.

Binding Energy and Interaction Between the Docked Compounds With the Amino Acids in the Active Site of Tubulin and Topoisomerase.

Compounds	Binding energy (kJ/mol)		Interaction with residues
Compounds	Tubulin	Topoisomerase	Tubulin	Topoisomerase
8a	−17.73	−15.85	H-bond: Val181 α, Asp251 β Hydrophobic: Ala180 α, Asn101 α, Met259 β, Lys352 β, Ala316 β, Leu255 β, Leu248 β, Ala250 β.	H-bond: Asp479 Hydrophobic: Arg503, Gly478, DCC
8b	−16.50	−17.08	H-bond: Val181 α, Thr179 α Hydrophobic: Ala180 α, Met259 β, Cys241 β, Lys352 β, Ala316 β, Leu255 β, Leu242 β, Ala354 β, Ala250 β, Asp251 β, Leu248 β	H-bond: Asp479, Ser480 Hydrophobic: Arg503, Gly478, Leu502, DCC
Colchicine	−21.14		H-bond: Val181 αHydrophobic: Ala180 α, Met259 β, Cys241 β, Lys352 β, Ala316 β, Leu255 β, Leu242 β, Ala250 β, Val315 β, Ile318 β, Ile378 β, Ala354 β, Asn350 β, Asp251 β, Leu248 β
Etoposide (1)		−19.74		H-bond: Asp479, Gln778, DC8C, DG13FHydrophobic: Arg503, Met782, Gly478, DA12F, DT9D, DG10D

On the other hand, etoposide (1), which is the co-crystallized ligand found in the PDB complex 3QX3, provided interactions with both topoisomerase and DNA chain domains. The results highlight the role of the 3 hydrogen bonds between the p-OH-phenyl toward Asp479, the oxygen atom of the glycone part with DC8C and DG13F, and the oxygen atom of the lactone ring with Gln778. Besides, multiple hydrophobic interactions of etoposide (1) with DA12F, DT9D, and DG10D of DNA and Arg503, Met782, and Gly478 of the topoisomerase domain could keep the ligand stable inside the pocket. Likewise, 8a and 8b also participated in the same key interactions provided by etoposide (1). There are hydrogen bonds between para-substituted groups of the phenyl ring with Asp479, and stacking interactions between the quinone ring with Arg503 and Gly478 (Figure 4). The binding energy values calculated for 8a and 8b are acceptable, being −15.9 and −17.1 kJ/mol, respectively (Table 2). In summary, 8a and 8b can be classified as classical tubulin and topoisomerase inhibitors.

Figure 4.

Interactions between compounds 8a and 8b with active site of topoisomerase.

Conclusions

The efficient and straightforward preparation of 2 new fluorinated podophyllotoxin–nạpthoquinones is described, using a microwave-assisted multicomponent approach employing 2-amino-1,4-naphthoquinone, fluorinated benzaldehydes, and tetronic acid. Subsequent cytotoxic assessment in KB, HepG2, A549, MCF7, and Hek-293 cell lines, together with the investigation of their interactions with the amino acids in the active site of tubulin and topoisomerase implied their potential for further elaboration toward novel anticancer agents.

Materials and Methods

The synthesis procedure for compounds 8a and 8b, the MTT assay protocol, and molecular docking protocol are provided in the supporting information.

11-(3-Fluoro-4-Hydroxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]Quinolin-1,5,10(3H)-Trione (8a)

Yield 275 mg (73%), orange solid, mp. 302°C. IR (KBr) ν_max/cm⁻¹ 3351, 3102, 3037, 2948, 1745, 1667, 1629, 1589, 1517, 1493, 1478, 1439, 1397, 1340, 1297, 1194, 1113, 1024, 1000, 932, 792, 771, 730, 601, 577. ¹H NMR (DMSO-d₆, 600 MHz): δ 10.58 (1H, s, -NH), 9.66 (1H, s, -OH), 8.05 (1H, dd, J = 7.8, 1.2 Hz, H-6), 7.90 (1H, dd, J = 7.8, 1.2 Hz, H-9), 7.83 (1H, td, J = 7.8, 1.2 Hz, H-8), 7.80 (1H, td, J = 7.8, 1.2 Hz, H-7), 7.05 (1H, dd, J = 12.6, 2.4 Hz), 6.93 (1H, dd, J = 8.4, 2.4 Hz), 6.81 (1H, t, J = 8.4 Hz), 4.97 (1H, d, J = 16.8 Hz, H-3^a), 4.91 (1H, s, H-11), 4.88 (1H, dd, J = 16.8, 1.2 Hz, H-3^b). ¹³C NMR (DMSO-d₆, 125 MHz) δ 182.1 (C-10), 179.5 (C-5), 171.1 (C-1), 155.8 (C-3a), 151.7 (1C, d, J = 238.75 Hz, C-3’), 143.5 (1C, d, J = 11.25 Hz, C-4’), 139.2 (C-4a), 136.0 (1C, d, J = 5.0 Hz, C-1’), 134.9 (C-8), 133.3 (C-7), 131.9 (C-9a), 130.3 (C-5a), 125.9 (C-6), 125.7 (C-9a), 124.1 (C-6’), 118.1 (C-10a), 117.3 (1C, d, J = 2.5 Hz, C-5’), 115.7 (1C, d, J = 18.75 Hz, C-2’), 101.8 (C-11a), 66.1 (C-3), 34.0 (C-11). HRESIMS (ESI): Found m/z 378.0775 [M + H]⁺, calcd. for [C₂₁H₁₃FNO₅]⁺: 378.0773, and m/z 395.1042 [M+NH₄]⁺, calcd. for [C₂₁H₁₆FN₂O₅]⁺: 395.1038.

11-(4-(Difluoromethoxy)-3-Hydroxyphenyl)-4,11- dihydrobenzo[g]furo[3,4-b]Quinolin-1,5,10(3H)-Trione (8b)

Yield 289 mg (68%), orange solid, mp. 175°C. IR (KBr) ν_max/cm⁻¹ 3311, 2971, 2942, 2900, 2710, 1742, 1653, 1601, 1570, 1502, 1433, 1393, 1349, 1301, 1264, 1236, 1194, 1115, 1049, 1023, 1001, 957, 828, 788, 724, 678, 552. ¹H NMR (DMSO-d₆, 600 MHz): δ 10.65 (1H, s, -NH), 9.78 (1H, s, -OH), 8.06 (1H, dd, J = 7.8, 1.2 Hz, H-6), 7.91 (1H, dd, J = 7.8, 1.2 Hz, H-9), 7.83 (1H, td, J = 7.2, 1.2 Hz, H-8), 7.81 (1H, td, J = 7.2, 1.2 Hz, H-7), 6.97 (1H, d, J = 7.8 Hz), 6.94 (1H, d, J = 1.8 Hz, H-2’), 6.93 (1H, t, J = 75 Hz, H-7’), 6.74 (1H, dd, J = 8.4, 2.4 Hz), 4.97 (1H, d, J = 16.2 Hz, H-3^a), 4.91 (1H, s, H-11), 4.90 (1H, dd, J = 16.2, 0.6 Hz, H-3^b). ¹³C NMR (DMSO-d₆, 150 MHz) δ 182.0 (C-10), 1179.5 (C-5), 171.1 (C-1), 155.8 (C-3a), 148.4, 142.7, 139.3 (C-4a), 137.2 (1C, d, J = 3.0 Hz, C-4’), 135.0 (C-8), 133.4 (C-7), 131.8 (C-9a), 130.2 (C-5a), 126.0 (C-6), 125.8 (C-9a), 121.5, 118.9, 118.2 (C-10a), 116.8, 116.6 (1C, t, J = 256.5 Hz, C-7’), 101.9 (C-11a), 66.1 (C-3), 34.4 (C-11). HRESIMS (ESI): Found m/z 426.0800 [M + H]⁺, calcd. for [C₂₂H₁₄F₂NO₆]⁺: 426.0784, and m/z 443.1070 [M+NH₄]⁺, calcd. for [C₂₂H₁₇F₂N₂O₆]⁺: 443.1050.

The HRESIMS and NMR spectra for products 8a and 8b are shown in Supplemental Figures S1 to S6.

Supplemental Material

sj-doc-1-npx-10.1177_1934578X231153733 - Supplemental material for Synthesis, Molecular Docking, and Cytotoxic Evaluation of Fluorinated Podophyllotoxin Derivatives

Supplemental material, sj-doc-1-npx-10.1177_1934578X231153733 for Synthesis, Molecular Docking, and Cytotoxic Evaluation of Fluorinated Podophyllotoxin Derivatives by Nguyen Ha Thanh, Le Quang Bao, Hai Pham-The, Dang Thi Tuyet Anh and Phan Van Kiem in Natural Product Communications

Footnotes

Acknowledgements

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

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.

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).

ORCID iDs

Nguyen Ha Thanh

Phan Van Kiem

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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Synthesis,Molecular Docking,and Cytotoxic Evaluation of Fluorinated Podophyllotoxin Derivatives

Abstract

Keywords

Introduction

Results and Discussion

Conclusions

Materials and Methods

11-(3-Fluoro-4-Hydroxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]Quinolin-1,5,10(3H)-Trione (8a)

11-(4-(Difluoromethoxy)-3-Hydroxyphenyl)-4,11- dihydrobenzo[g]furo[3,4-b]Quinolin-1,5,10(3H)-Trione (8b)

Supplemental Material

sj-doc-1-npx-10.1177_1934578X231153733 - Supplemental material for Synthesis, Molecular Docking, and Cytotoxic Evaluation of Fluorinated Podophyllotoxin Derivatives

Footnotes

Acknowledgements

Declaration of Conflicting Interests

Funding

ORCID iDs

Supplemental Material

References

Supplementary Material