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-Valverde^2*, 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, Thr_552, 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, Thr_556, 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, Val_535,Tyr₅₄₂, Leu₅₅₂, Leu₅₅₉
20	Val₄₁₈, Ile₄₁₉, Leu₅₃₂, Val_535,Leu₅₅₂, Leu₅₅₉
21	Leu₄₁₅, Val₄₁₈, Ile₄₁₉, Ala₄₂₂, Leu₅₃₂, Val_535,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.