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Clinical Cancer Investigation Journal
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ARTICLE
Year: 2023   |   Volume: 12   |   Issue: 4   |   Page: 4-9     View issue

Theoretical Evaluation of Furanone and its Derivatives for the Treatment of Cancer Through Eag-1 Inhibition

Magdalena Alvarez-Ramirez1, Lauro Figueroa-Valverde2*, FranciscoDiaz-Cedillo3, Marcela Rosas-Nexticapa1, Maria Lopez-Ramos2, Virginia Mateu-Armand1, Lopez-Gutierrez Tomas2

1Nutrition Laboratory, Faculty of Nutrition, University of Veracruz, Medicos y s/n Odontologos 910210, Unidad del Bosque, Xalapa, Mexico. 2Pharmacochemistry Research Laboratory, Faculty of Biological-Chemical Sciences, University Autonomous of Campeche; Humberto Lanz Cárdenas s/n, Ex Hacienda Kalá, C.P. 24085, Campeche, Mexico. 3Laboratory of Organic chemistry, Biological Sciences, National Politechnic Institute; Prolongacion de Carpio y Plan de Ayala s/n, Col. Sto Tomas, 11340, Mexico.


Abstract

Several studies suggest that some drugs such as astemizole and tetrandine can inhibit the expression of Eag-1 in cancer cells. Analyzing these data, this study aimed to evaluate the theoretical interaction of furanone (compound 1) and its derivatives (compounds 2 to 30) with Eag-1 using the 7CN1 protein as a theoretical model; in addition, astemizole, tetrandine, N-(4-(2-(Diethylamino)ethoxy)phenyl)-2-nitro-4-(trifluoromethyl)-aniline (DNTA), 1-Dimethylamino-3-[4-(2-nitro-4-trifluoromethyl-phenyl-amino)-phenoxy]-propan-2-ol (ZVS-08), and 3-Chloro-N-{2-[3,5-dibromo-4-(3-di-methyl-amino-propoxy)-phenyl]-ethyl}-4-metho-xy-benzamide (PD) were used as controls in the DockingServer software. Results showed that interaction of compounds 1-30, DNTA, ZVS-08, and PD with 7CN1 protein surface involves different aminoacid residues. Besides, inhibition constant was lower for furanone derivatives 7, 12, 16, 20, 25, 26, 29, and 30 compared to astemizole, tetrandine, DNTA, ZVS-08, and PD. These data suggest that furanone derivatives 7, 12, 16, 20, 25, 26, 29, and 30 could act as Eag-1 inhibitors in cancer cells. Therefore, these furenone derivatives could be good candidates for the treatment of cancer.

Keywords: Cancer, Furanone, Eag-1, Docking


Introduction

Cancer is one of the main public health problems worldwide;[1-4] this clinical pathology can be conditioned by several factors such as alcohol,[5, 6] obesity,[7, 8] cigarette smoking,[9, 10] dietary fatty acid pattern[11, 12] and some genetic factors.[13-15] In addition, other data indicates that the Eag-1 (ether-à-go-go-1; member of the voltage-dependent potassium channel family) may be involved in cancer cell growth.[16, 17] For example, a study showed the expression of Eag-1 potassium channels in gastric cancer patients using immunohistochemistry methods.[18, 19] Another study shows that both Eag-1 mRNA and protein expression is increased in A549 lung cancer cells undergoing epithelial-to-mesenchymal transition (a likely mechanism by which tumor cells become malignant) induced by TGFβ1 (growth factor beta).[20, 21] Besides, a report displayed that Eag-1 might be involved in the pathophysiological processes of prostate cancer tissue using both reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IM) methods.[22, 23] Other studies carried out in a population of 12 Chinese women with breast cancer showed that this clinical pathology was associated with Eag-1 and HIF-1α expression.[24] In addition, Eag-1 expression was determined in esophageal squamous cell carcinomas tissues through both RT-PCR and IM methods.[25, 26] To try to inhibit the cancer cells' growth some drugs such as astemizole have been used; for example, a study suggests that astemizole may decrease cervical cancer cell lines growth (HeLa, SiHa, CaSki, INBL, and C-33A) by decreasing Eag1 expression.[27-29] Other data suggest that imipramine may produce changes in Eag1 expression on a prostate cancer cell line (DU145).[30, 31] Furthermore, a study showed that calcitriol can inhibit Eag1 expression and the proliferation of human breast cancer.[32, 33] All these data suggest that some drugs can inhibit the Eag1 expression translated as a decrease in cancer cell growth; however, the interaction of these drugs with Eag1 is not very clear on cancer cells. Analyzing these data, this study aimed to evaluate the possibility that a series of furanone derivatives could interact with Eag1 using a 7CN1 protein as a theoretical model. Besides, astemizole, tetrandine, DNTA, ZVS-08, and PD drugs were used as controls on the DockingServer program.

 

Materials and Methods

Methodology general

 

Figure 1 shows the chemical structure of furanone and its derivatives which were used as theoretical tools to assess their potential interaction with 7CN1.

 

Figure 1. Chemical structure of furenone (1) and their derivatives (2-31). Source: ChemPub (https://pubchem.ncbi.nlm.nih.gov/).

1 = Dihydro-furan-2-one

2 = 3H-Furan-2-one

3 =5H-Furan-2-one

4 = Dihydro-3-amino-2-(3H)-furanone

5 = Dihydro-2,2,5,5-tetramethyl-3(2H)-furanone

6 = (S)-(-)-5-Hydroxymethyl-2(5H)-furanone

7 = (Z-)-4-Bromo-5-(bromomethylene)-2(5H)-fura-none

8 = 2,2,4,5-tetraphenyl-3(2H)-furanone

9 = 2,2-Dimethyl-3(2H)-furanone

10 = 2,2-Dimethyl-5-phenyl-dihydro-furan-3-one

11 = 2,5-Dimethyl-3(2H)-furanone

12 = 2,5-Dimethyl-4-methoxy-3(2H)-furanone

13 = 2-Hydroxy-2,4,5-triphenyl-3(2H)-furanone

14 = 2-Methoxy-2,4-diphenyl-3(2H)-furanone

15 = 2-Methyltetrahydro-3-furanone

16 = 3,3,5-trimethyldihydro-2(3H)-furanone

17 = 3-(Triphenylphosphoranylidene)dihydro-2(3H)-furanone

18 = 3,4,5-Triphenyl-2(3H)-furanone

19 = 3,4-Dibromo-2(5H)-furanone

20 = 3,4-Dichloro-2(5H)-furanone

21 = 3-Allyldihydro-2(3H)-furanone

22 = 3-Bromo-5-(Diphenylmethylene)-2(5H)-furo-none

23 = 3-Methyl-2(5H)-furanone

24 = 4-Acetoxy-2,5-dimethyl-3(2H)furanone

25 = 4-Anilino-2(5H)-furanone

26 = 4-Hydroxy-2,5-dimethyl-3(2H)-furanone

27 = 4-Methoxy-2(5H)-furanone

28 = 4-[(Cyclohexylamino)methyl]-3,3-diphenyl-dihydro-2(3H)-furanone

29 = 5-Ethyl-3-hydroxy-4-methyl-2(5H)-furenone

30 = 5-Ethyl-4-hydroxy-2-methyl-3(2H)-furanone

 

Ligand-protein complex

The interaction of furanone and their derivatives with the Eag1 protein surface was determined using 7CN1 (PDB DOI:  https://doi.org/10.2210/pdb7CN1/pdb) protein[34] as a theoretical model. In addition, to evaluate the thermodynamic parameters involved in coumarin derivative-protein complex formation, the DockingServer program was used.[35]

Pharmacokinetics parameter

Theoretical pharmacokinetics involved in the chemical structure of furanone derivatives (7, 12, 16, 20, 25, 26, 29, and 30) were determined using the SwissADME software.[36]

Toxicity analysis

 

Toxicity evaluation for furanone derivatives 7, 12, 16, 20, 25, 26, 29, and 30 was determined using GUSAR software.[37]

Results and Discussion

Protein-ligand evaluation

In the literature, there are some methods to predict the interaction of some drugs with EAG-1 such as Autodock[38] and Rosetta[39]. In this way, a study showed that tetrandrine directly interacted with Eag1 through the amino acids Ile550, Thr552, and Gln557 surface[40]. Another study showed that procyanidin B1 could interact with the EAG-1 surface which involves amino acid residues such as Ile550, Thr552, and Gln557. Analyzing these data, in this research furanone and its derivatives were used to evaluate their interaction with EAG-1 using 7CN1 protein as a theoretical model. The results shown in Table 1 indicate that the interaction of furanone and their derivatives with the 7CN1 protein surface could involve some different aminoacid-residues compared to astemizole, tetrandine, DNTA, ZVS-08, and PD drugs.

Table 1. Aminoacid residues involved in the coupling of furenone and their derivatives with 7CN1 protein surface using DockingServer

Compounds

Aminoacid residues

Astemizole

Pro426, Leu529, Leu532, Val533, Thr556, Leu559, Trp563, Cys566, Ile567

Tetrandine

Leu529, Leu532, Val533, Ile560, Trp563, Ile567

DNTA

Leu529, Leu532, Val533, Val535, leu552, Thr556, Trp563

ZVS-08

Pro426, Leu529, Leu532, Val533, Ala536, Trp563, Ile567

PD

Leu532, Ile560, Trp563, Leu564, Ile567, Ile647

1

Asp411, Ile414, Leu415, Val418, Phe463, Arg534, Val535, Lys538, Tyr542

2

Asp411, Ile414, Leu415, Val418, Phe463, Arg534, Val535, Lys538, Tyr542

3

Asp411, Ile414, Leu415, Val418, Phe463, Arg534, Val535, Lys538, Tyr542

4

Ile419, , Leu552, Cys555, Thr556, Leu559

5

Val418, Ile419, Ala422, Leu532, Val535, Leu559

6

Leu415, Val418, Ile419, Ala422, Leu532, Val535, Leu552, Leu559

7

Leu415, Val418, Ile419, Leu532, Val535, Tyr542 Leu552, Cys555, Thr556, Leu559

8

Ile419, Ala422, Leu532, Val535, Ala536, Leu552, Cys555, Thr556, Leu559, Trp563

9

Leu415, Val418, Ile419, Val535, Tyr542, Leu552

10

Thr425, Pro426, Ala429, Thr526, Leu529, Trp563, Cys566, Ile567

11

Val418, Ile419, Ala422, Leu532, Val535, Leu552, Leu559

12

Leu415, Val418, Ile419, Ala422, Leu532, Val535, Leu552, Leu559

13

Ile419, Leu532, Val535, Ala536, Leu552, Cys55, Thr556, Leu559, Trp563

14

Leu415, Val418, Ile419, Val535, Tyr542, Leu552, Leu553, Thr556, Leu559

15

Leu415, Val418, Ile419, Val535, Tyr542, Leu552

16

Val418, Ile419, Ala422, Leu532, Val535, Leu552, Leu559

17

Ile419, Ala422, Leu532, Val535, Ala536, Leu552, Thr556, Leu559, Trp563

18

Leu415, Val418, Ile419, Val535, Leu539, Leu552, Cys555Thr556, Leu559, Trp563

19

Leu415, Val418, Ile419, Leu532, Val535, Tyr542, Leu552, Leu559

20

Val418, Ile419, Leu532, Val535, Leu552, Leu559

21

Leu415, Val418, Ile419, Ala422, Leu532, Val535, Tyr542, Leu559

22

Pro426, Leu529, Leu532, Trp563, Ile567

23

Leu415, Val418, Ile419, Val535, Tyr542, Leu552

24

Val418, Ile419, Ala422, Leu532, Val535, Leu552, Cys555, Thr556, Leu559

25

Val418, Ile419, Ala422, Leu532, Leu552, Thr556, Leu559

26

Val418, Ile419, Leu532, Leu552, Leu559

27

Leu415, Val418, Ile419, Ala422, Leu532, Val535, Tyr542, Leu552

28

Thr425, Pro426, Ala429, Thr526, Leu529, Leu532, Trp563, Cys566, Ile567

29

Val418, Ile419, Ala422, Leu532, Leu552, Leu559

30

Leu415, Val418, Ile419, Ala422, Leu532, Val535, Leu552, Leu559

DNTA = N-(4-(2-(Diethylamino)ethoxy)phenyl)-2-nitro-4-(trifluoromethyl)-aniline; ZVS-08 = 1-Dimethylamino-3-[4-(2-nitro-4-trifluoromethyl-phenyl amino)-phenoxy]-propan-2-ol; PD = 3-Chloro-N-{2-[3,5-dibromo-4-(3-di-methylamino-propoxy)-phenyl]-ethyl}-4-methoxy-benzamide.

However, it is important to mention that this interaction may involve some thermodynamic parameters such as the free energy of binding, electrostatic energy, total intermolecular energy, and 4) Van der Waals (vdW) + hydrogen bond (H-bond) + desolvation energy.[35] For this reason, in this study, some thermodynamic parameters involved in the interaction of furanone and its analogs with the 7CN1 protein surface were evaluated using the DockingServer program. The results (Table 2) display differences in bond-energy levels for furanone and their derivatives compared with astemizole, tetrandibne, DNTA, ZVS-08, and PD. Besides, the inhibition constant (Ki) was lower for furonone derivatives 7, 12, 16, 20, 25, 26, 29 and 30 compared to PD. Other results indicate that Ki for furanone derivatives 1-9, 11-13, 15, 16. 18-21, 23, and 25-30 were lower compared to astemizole. All these data suggest that these furanone derivatives (Figure 2) could act as EAG-1 inhibitors, resulting in a decrease in cancer cell growth.

Table 2. Thermodynamic parameters involved in the interaction of coumarin and their derivatives with 7CN1 protein surface using DockingServer software.

Compound

A

B

C

D

E

F

Aztemisole

-5.91

46.76

-8.29

0.38

-7.91

828.65

Tetrandine

-5.21.

151.33

-6.95

0.72

-6.22

769.28

DNTA

-4.65

389.22

-6.19

0.44

-5.75

728.23

ZVS-08

-5.41

108.97

-6.10

0.44

-5.66

638.51

Purperealidin analog

-3.57

2.42

-5.29

0.29

-4.99

674.35

1

-2.82

8.59

-3.00

0.18

2.82

220.51

2

-2.73

10.05

-2.47

-0.25

-2.73

217.38

3

-3.09

6.42

-2.75

-0.34

-3.09

217.50

4

-2.23

23.02

-2.93

0.39

-2.53

323.42

5

-4.15

910

-4.16

0.01

-4.15

418.33

6

-3.19

4.56

-2.88

-0.01

-2.89

321.75

7

-4.05

1.08

-4.04

0.00

-4.05

306.14

8

-6.48

17.81

-7.66

0.01

-7.64

734.20

9

-3.03

5.96

-3.03

0.00

-3.03

326.04

10

-5.16

164.40

-5.46

0.00

-5.46

473.79

11

-3.66

2.09

-3.20

-0.46

-3.66

333.45

12

-3.61

2.25

-3.46

-0.45

-3.91

418.17

13

-6.12

32.71

-7.01

0.00

-7.01

678.55

14

-5.56

83.62

-6.43

0.00

-6.44

612.84

15

-3.01

6.20

-3.01

0.00

-3.01

305.43

16

-3.81

1.60

-3.81

0.00

-3.81

354.91

17

-5.50

93.62

-6.89

0.01

-6.88

698.70

18

-6.47

18.23

-7.39

-0.01

-7.40

656.12

19

-3.21

4.45

-3.21

0.00

-3.21

277.67

20

-4.04

1.10

-4.04

0.00

-4.04

361.31

21

-3.42

3.10

-4.01

0.00

-4.00

365.16

22

-5.21

152.69

-5.84

-0.01

-5.85

512.90

23

-2.73

9.95

-2.74

-0.01

-2.73

303.10

24

-4.21

823.80

-4.31

-0.44

-4.75

453.04

25

-3.60

2.29

-4.20

0.00

-4.19

477.50

26

-3.66

2.07

-3.22

-0.44

-3.66

353.21

27

-2.56

13.24

-2.85

-0.01

-2.86

319.19

28

-7.14

5.83

-7.66

0.41

-7.25

605.97

29

-3.85

1.50

-3.70

-0.45

-4.15

403.21

30

-3.64

2.14

-3.49

-0.45

-3.94

387.40

A = Est: Free Energy of Binding (kcal/mol); B = Inhibition Constant, Ki (mM); C = vdW + Hbond + desolv Energy (kcal/mol); D = Electrostatic Energy (kcal/mol); E = Total Intermolec. Energy (kcal/mol); F = Interact. Surface; DNTA = N-(4-(2-(Diethylamino)- ethoxy)phenyl)-2-nitro-4-(trifluoromethyl)aniline; ZVS-08 = 1-Dimethylamino-3-[4-(2-nitro-4-trifluoromethyl-pheny-lamino)-phenoxy]-propan-2-ol.