Analysis of Interaction between Twenty-Seven Pyrimidinone Derivatives with XIAP Using a Theoretical Model

Lauro Figueroa-Valverde; Francisco Diaz-Cedillo; Marcela Rosas-Nexticapa; Catalina Cervantes-Ortega; Magdalena Alvarez-Ramirez; Virginia Mateu-Armand; Maria Lopez-Ramos

doi:10.51847/2bWWpF0Bdl

ARTICLE

Year: 2023 | Volume: 12 | Issue: 3 | Page: 13-18 View issue

Analysis of Interaction between Twenty-Seven Pyrimidinone Derivatives with XIAP Using a Theoretical Model

Lauro Figueroa-Valverde^1*, Francisco Diaz-Cedillo², Marcela Rosas-Nexticapa³, Catalina Cervantes-Ortega³, Magdalena Alvarez-Ramirez³, Virginia Mateu-Armand³, Maria Lopez-Ramos¹

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

Abstract

For several years, several drugs have been used to treat different types of cancer; however, some of these drugs can cause side effects, such as high blood pressure, liver damage, and erectile dysfunction. In the search for new therapeutic alternatives, some compounds have been developed for the treatment of this clinical pathology; however, the interaction of these drugs with some biomolecules involved in the development of cancer is very unclear. Analyzing this data, this investigation aimed to evaluate the possible theoretical interaction of some pyrimidinone derivatives (compounds 1 to 27) on the X-linked inhibitor of apoptosis protein (XIAP) involved in cancer using the Docking model. The results showed that some pyrimidinone derivatives (1-6, 10, 11, 14, 15, 22-24, 26, and 27) could interact with the XIAP protein surface. In conclusion, these data suggest that some pyrimidinone derivatives can produce changes in the biological activity of XIAP. Therefore, these pyrimidinone derivatives could be good candidates to treat cancer.

Keywords: Cancer, Pyrimidinone derivatives, XIAP, Docking

Introduction

Several data indicate that cancer is one of the main causes of death worldwide, which translates into a decreased life expectancy of the population.^[1-9] This clinical pathology has been increasing in both developed and developing countries due to various factors involved such as aging and population growth.^[10-13] In addition, some biomolecular signaling systems are activated to produce cancer; for example, there are some studies indicating that X-linked inhibitors of apoptosis protein (XIAP) may regulate cell death signaling pathways through the binding and inhibition of caspases.^[14-16] In addition, other data suggest that XIAP may be involved in the development of several types of cancer.^[17-23] In this way, some drugs have been developed; for example, a study showed that Clioquinol (5-chloro-7-iodo-8-quinolinol) induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP) translated as a decrease of prostate cancer.^[24] Other data showed that compound (3S,6S,9R,10aR)-6-((S)-2-(Methylamino)propanamido)-5-oxo 9-(2-phenylacetami-do)-N-((R)-1,2,3,4-te-trahydronaphthalen-1-yl)decahydropyrrolo [1,2-a]azocine-3-carboxamide decreases the growth of cancer cells (MDA-MB-231) through XIAP inhibition.^[25] Besides, a report displayed the synthesis of a series of benzodiazepinones as XIAP selective inhibitors for the treatment of cancer using an in vitro model.^[26] In addition, a study carried out on human gastric cancer cell lines AGS (adenocarcinoma), KATO-III (signet-ring cell carcinoma), and NCI-N87 (gastric carcinoma) showed that Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquino-ne) can decrease the expression of XIAP translated as cell cycle arrest at the S and G2/M phases and apoptosis.^[27] Furthermore, a study showed that embelin acts as an inhibitor of XIAP using human prostate cancer cell lines (PC-3, LNCap, CL-1, DU-145).^[27] Other data show that some diazabicyclic derivatives inhibit the expression of XIAP using some cancer cell lines such as MDA-MB-231 and SK-OV-3.^[28] All these data suggest that some drugs can decrease the expression of XIAP, which translates as changes in the growth of some cancer cells; however, there is little information in the literature on the interaction of pyrimidinone with XIAP protein.

Perhaps this is due to the diverse experimental designs that focus on multiple

molecular mechanisms involved in cancer. Analyzing this hypothesis, the objective of this study was to evaluate the interaction of twenty-seven pyrimidinone derivatives with XIAP using a theoretical model.

Materials and Methods

Twenty-seven pyrimidinone derivatives previously reported in PubChem.^[29] (Figure 1) were used to evaluate the possible interaction with X-linked inhibitor of apoptosis protein (XIAP) as follows:

Figure 1. Chemical structure of XIAP inhibitors(A, B, and C) and pyrimidinone derivatives (1-27)

A = (3S,6S,9R,10AR)-6-((S)-2-(Methylamino)propanamido)-5-oxo-9-(2-phenylacetami- do)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azo-cine-3-car-boxamide.^[25]

B = N-(3,4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2,3,3a,4,5,9bhexahydrofuro [3,2-c]quinoline-8-sulfonamide.^[30]

C = (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-cyanophenyl)(methyl)amino)-2-hydroxy-2-methylpropanamide).^[31]

1 = 1,3-Dimethyl-3,4,5,6,-tetrahydro-2(1H)-pyrimidinone

2 = 1-isopropyltetrahydro-2(1H)-pyrimidinone

3 = 2-(1,4-Diazepan-1-yl)-6-(methoxymethyl)-4(3H)-pyrimidinone

4 = 2-(1,4-Diazepan-1-yl)-6-ethyl-4(3H)-pyrimidinone

5 = 2-(1,4-Diazepan-1-yl)-6-methyl-4(3H)-pyrimidinone

6 = 2-(1,4-Diazepan-1-yl)-6-propyl-4(3H)-pyrimidinone

7= 2-(Benzylamino)-4(3H)-Pyrimidinone

8= 2-(Methylsulfanyl)-6-propyl-4(3H)-pyrimidinone

9= 2-Amino-6-(4-fluorophenyl)-4(3H)-pyrimidinone

10= 2-ethoxy-4(3H)-pyrimidinone

11= 4,6-Dimethyl-2(1H)-Pyrimidinone

12= 4-Amino-1-benzyl-2(1H)-pyrimidinone

13= 4-Amino-1-[(3,5-dimethyl-4-isoxazolyl)methyl]-2(1H)-pyrimidinone

14= 5-Fluoro-2-ethoxy-4(1H)pyrimidinone

15= 5-Fluoro-6-methoxy-2(1H)-pyrimidinone

16= 6-(3-Bromophenyl)-1-methyl-5-(3-methyl-5-isoxazolyl)-2(1H)-pyrimidinone

17= 6-(Chloromethyl)-2-(2-pyrazinyl)-4(3H)-pyrimidinone

18= 6-(Chloromethyl)-2-(3,4-difluorophenyl)-4(3H)-pyrimidinone

19= 6-(Chloromethyl)-2-(3-chlorophenyl)-4(3H)-pyrimidinone

20= 6-(Chloromethyl)-2-(4-ethylphenyl)-4(3H)-pyrimidinone

21= 6-(Chloromethyl)-2-(4-methoxyphenyl)-4(3H)-pyrimidinone

22= 6-(Dimethylamino)-5-fluoro-2(1H)-pyrimidinone

23= 6-(Methoxymethyl)-2-(1-piperazinyl)-4(3H)-pyrimidinone

24= 6-Amino-2-(methylsulfanyl)-4(3H)-pyrimidinone

25= 6-Butyl-2-(1-piperazinyl)-4(3H)-pyrimidinone

26= 6-Ethyl-2-(1-piperazinyl)-4(3H)-pyrimidinone

27= 6-Ethyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone

Ligand-protein evaluation

The interaction of twenty-seven pyrimidinone derivatives with XIAP was evaluated using 4ic2^[32] protein as a theoretical model using some XIAO inhibitors (compounds A, B, and C)^{[25, 30, 31]} as control. In addition, binding energy involved in the interaction of pyrimidinone derivatives with the 4ic2 protein surface was evaluated using DockingServer software.^[33]

Pharmacokinetics parameter

Pharmacokinetic parameters were determined using the SwissADME software.^[34]

Toxicity evaluation

The possible toxicity produced by pyrimidinone derivatives (2, 5, 9, 11, 13, and 15) was determined using the GUSAR software.^[35]

Results and Discussion

The literature reports are indicating that some compounds can produce changes in the biological activity of XIAP,^[24-27] resulting in a decrease in the growth of cancer cells. However, there are data on the interaction of pyrimidinone derivatives with XIAP, which translates into insufficient information on the effect that these compounds could produce on cancer cells.

Protein-ligand analysis

This study aimed to evaluate the interaction of twenty-seven pyrimidinone derivatives with XIAP using 4ic2 protein and compounds A, B, and C (Figure 1) as theoretical tools in a Docking model.^[33] The results showed in Table 1 and Figure that different amino acid residues are involved in the interaction of pyrimidinone derivatives with XIAP; this data suggest that this interaction is due to different functional groups involved in the chemical structure of each pyrimidinone derivative (Table 1, Figures 2 and 3).

Table 1. Aminoacid residues are involved in the interaction of pyrimidinone derivates with the 4ic2-protein surface
Compound	Aminoacid residues
A	Glu₄₄₇; Lys₄₄₈; Lys₄₅₁; Asn₄₅₇; Ile₄₅₈; Leu₄₆₈; Met₄₈₃; Ile₄₉₄; Met₄₉₆
B	Leu₄₄₄; Glu₄₄₇; Lys₄₄₈; Lys₄₅₁; Ile₄₅₈; Leu₄₆₈; Met₄₉₆
C	Lys₄₄₈; Ile₄₅₈; Leu₄₆₈; Met₄₈₃; Ile₄₉₄; Phe₄₉₅; Met₄₉₆
1	Lys₄₄₈; Asn₄₅₇; Ile₄₅₈; Leu₄₆₈; Ile₄₉₄; Met₄₉₆
2	Lys₄₄₈; Asn₄₅₇; Ile₄₅₈; Ile₄₉₄; Met₄₉₆
3	Leu₄₄₄; Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Leu₄₆₈; Met₄₉₆
4	Leu₄₄₄; Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Leu₄₆₈; Met₄₉₆
5	Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Leu₄₆₈; Met₄₉₆
6	Leu₄₄₄; Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Met₄₉₆
7	Lys₄₄₈; Ile₄₅₈; Ala₄₅₉; Leu₄₆₈; Ile₄₉₄; Phe₄₉₅; Met₄₉₆
8	Lys₄₄₈; Ile₄₅₈; Leu₄₆₈; Ile₄₉₄; Met₄₉₆
9	Leu₄₄₄; Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Ile₄₉₄; Met₄₉₆
10	Lys₄₄₈; Ile₄₅₈; Ala₄₅₉; Ile₄₉₄; Met₄₉₆
11	Ile₄₅₈; Ala₄₅₉; Ile₄₉₄; Phe₄₉₅; Met₄₉₆
12	Lys₄₄₈; Asn₄₅₇;Ile₄₅₈; Ala₄₅₉; Ile₄₉₄; Phe₄₉₅; Met₄₉₆
13	Glu₄₄₇; Ile₄₅₈; Gly₄₆₆; His₄₆₇; Leu₄₆₈
14	Lys₄₄₈; Ile₄₅₈; Ile₄₉₄; Met₄₉₆
15	Lys₄₄₈; Ile₄₅₈; Ala₄₅₉; Ile₄₉₄; Met₄₉₆
16	Leu₄₄₄; Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Leu₄₆₈; Met₄₉₆
17	Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Leu₄₆₈; Ile₄₉₄; Met₄₉₆
18	Lys₄₄₈; Asn₄₅₇; Ile₄₅₈; Leu₄₆₈; Ile₄₉₄; Phe₄₉₅; Met₄₉₆
19	Asn₄₅₇; Ile₄₅₈; Ala₄₅₉; Ile₄₉₄; Phe₄₉₅; Met₄₉₆
20	Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Leu₄₆₈; Ile₄₉₄; Met₄₉₆
21	Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Ala₄₅₉; Leu₄₆₈; Ile₄₉₄; Met₄₉₆
22	Lys₄₄₈; Asn₄₅₇; Ile₄₅₈; Ala₄₅₉; Ile₄₉₄; Met₄₉₆
23	Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Leu₄₆₈
24	Lys₄₄₈; Asn₄₅₇; Ile₄₅₈; Leu₄₆₈; Ile₄₉₄; Met₄₉₆
25	Leu₄₄₄; Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Leu₄₆₈
26	Leu₄₄₄; Glu₄₄₇; Lys₄₄₈; Ile₄₅₈; Leu₄₆₈; Met₄₉₆
27	Glu₄₄₇; Lys₄₄₈; Ile₄₅₈

Figure 2. The scheme showed different amino acid residues involved in the interaction of some pyrimidinone derivatives (1-6, 10, and 11) with a 4ic2-protein surface using DockingServer software.^[30]

Figure 3. Interaction of pyrimidinone derivatives (14, 15, 22, 23, 24, 26, and 27) with the 4ic2-protein surface involves several amino acid residues involved. Scheme visualized with the DockingServer software.^[30]

Binding energies

Some studies indicate that the ligand-protein interaction may depend on the energy levels such as the binding free energy, Electrostatic energy, total intermolecular energy, and Van der Waals forces.^[34] Analyzing these data, in this study, several thermodynamic factors involved in the interaction of pyrimidinone-derivatives with 4ic2 protein surface were evaluated using some XIAO-inhibitors such as compounds A, B, and C as controls. The results showed differences in the energy levels involved in the interaction of pyrimidinone derivatives with the 4ic2 protein surface compared with the controls (Table 2). Other results show that inhibition constant (Ki) pyrimidinone-derivatives (2, 3, 4, 6, 22, 24, and 26) was lower, compared with the controls (A, B, and C). In addition, the Ki for pyrimidinone-derivatives 1, 5, 10, 11, 14, 15, 23, and 27 were lower compared with the controls A and C. This phenomenon suggests that pyrimidinone derivatives such as 1-6, 10, 11, 14, 15, 22-22-24, 25, and 27 could inhibit the biological activity of XIAO protein translated as a possible decrease in prostate cancer levels.

Table 2. Thermodynamic parameters involved in the interaction of pyrimidinone derivates with the 4ic2-protein surface.
Compound	I	II	II	IV	V	VI
A	-6.88	9.04	-8.41	-0.14	-8.55	860.34
B	-7.79	1.94	-6.75	-0.73	-7.48	725.16
C	-5.60	78.24	-7.53	+0.05	-7.48	745.32
1	-3.15	4.92	-3.09	-0.06	-3.15	380.46
2	-3.94	1.30	-4.15	-0.09	-4.24	440.55
3	-3.89	1.40	-3.71	-0.93	-4.64	490.22
4	-3.92	1.35	-3.60	-1.00	-4.60	489.58
5	-3.64	2.13	-3.05	-0.89	-3.94	462.71
6	-3.88	1.43	-3.84	-0.92	-4.75	519.73
7	-5.20	153.39	-5.73	-0.06	-5.79	545.63
8	-4.17	873.21	-5.06	-0.02	-5.08	489.01
9	-4.98	222.21	-5.13	-0.15	-5.28	495.88
10	-3.33	3.65	-3.81	-0.10	-3.91	437.03
11	-3.51	2.68	-3.45	-0.06	-3.51	350.85
12	-4.97	227.23	-5.75	-0.12	-5.87	526.51
13	-4.16	886.57	-4.99	-0.05	-5.04	462.63
14	-3.52	2.62	-4.12	+0.01	-4.11	430.46
15	-3.68	2.01	-3.87	-0.10	-3.98	389.157
16	-5.40	109.27	-5.69	-0.18	-5.87	596.089
17	-4.47	533.28	-4.86	-0.35	-5.22	536.748
18	-5.46	100.33	-5.87	-0.34	-6.21	546.824
19	-5.22	148.08	-5.95	-0.06	-6.00	596.423
20	-5.32	126.81	-6.14	-0.22	-6.36	610.769
21	-4.58	436.01	-5.80	+0.04	-5.76	615.318
22	-3.76	1.74	-3.91	-0.15	-4.06	432.66
23	-3.65	2.10	-3.53	-1.01	-4.53	513.375
24	-3.79	1.66	-4.35	-0.04	-4.39	436.637
25	-4.49	507.65	-4.52	-1.03	-5.55	551.579
26	-4.00	1.17	-3.62	-0.99	-4.61	488.779
27	-3.66	2.09	-3.87	-0.09	-3.96	419.721

I = Free Energy of Binding (kcal/mol)

II = Inhibition Constant, Ki (mM)

III = Vander Waals forces + H-bond + desolv Energy (kcal/mol)

IV = Electrostatic Energy (kcal/mol)

V = Total Intermolecular Energy (kcal/mol)

VI = Interaction Surface

Pharmacokinetic analysis

In the literature, there are methods to predict some pharmacokinetic parameters for different drugs, such as PK/PD,^[36] MONOLIX,^[37]CXTMAIN,^[38] and SwissADME.^[39] In this research, some pharmacokinetic factors involved in pyrimidinone derivatives were evaluated using SwissADME software (Table 3). The results showed differences in gastrointestinal absorption and metabolism (involving different types of cytochrome P450 systems) of pyrimidinone derivatives compared with the controls. This data suggest that the pharmacokinetics of pyrimidinone derivatives could depend on their chemical structure.

Table 3. Pharmacokinetic parameters for pyrimidinone derivatives
Compound	i	ii	iii	iv		v	vi	vii	viii	ix
A	High	No	Yes	No		Yes	No	Yes	Yes	4.59
B	High	No	Yes	No		Yes	No	Yes	Yes	2.92
C	High	No	Yes	No		No	No	No	Yes	2.68
1	Low	No	No	No		No	No	No	No	0.33
2	High	No	No	No		No	No	No	No	0.73
3	High	No	Yes	No		No	No	No	No	0.11
4	High	No	Yes	No		No	No	No	No	0.72
5	High	No	Yes	No		No	No	No	No	0.43
6	High	No	Yes	No		No	No	No	No	1.04
10	High	No	No	No		No	No	No	No	0.65
11	High	No	No	No		No	No	No	No	0.73
14	High	Yes	No	No		No	No	No	No	0.95
15	High	No	No	No		No	No	No	No	0.56
22	High	No	No	No		No	No	No	No	0.61
23	High	No	Yes	No		No	No	No	No	0.11
24	High	No	No	No		No	No	No	No	0.23
26	High	No	Yes	No		No	No	No	No	0.72
27	High	No	No	No		No	No	No	No	1.24
i = GI absorption ii = BBB permeant iii = P-GP substrate iv = CYP1A2 inhibitor v = CYP2C19 inhibitor					vi = CYP2C9 inhibitor vii = CYP2D6 inhibitor viii = CYP3A4 inhibitor ix = Consensus Log P_O/W

Toxicity analysis

Some data in the literature indicate that several pyrimidinone derivatives can produce toxicity in different biological models.^[40-43] Analyzing these data, the possible toxicity produced by some pyrimidinone derivatives (2, 5, 9, 11, 13, and 15) was evaluated using the GUSAR software.^[35] The results showed that compounds A, B, and C require higher doses to produce toxicity (LD50) through the intraperitoneal route compared to pyrimidinone derivatives; however, pyrimidinone derivatives could produce different toxicity degrees through intravenous, oral, and subcutaneous routes compared with the controls. These data suggest that the toxicity could depend on the dose and routes of administration of each pyrimidinone derivative.

Table 4. Theorethical toxicity produced by compouns A,B,C, and pyrimidinone derivatives (1-6, 10, 11, 14, 15 22-24 26 and 27) using the Gussar software.
Compound	IP LD50 (mg/kg)	IV LD50 (mg/kg)	Oral LD50 (mg/kg)	SC LD50 (mg/kg)
A	959.00	58.74	1265.00	79.10
B	689.10	46.93	1943.00	396.00
C	757.70	82.31	974.40	695.40
1	126.40	33.69	797.20	169.20
2	137.70	89.46	871.30	151.60
3	94.22	128.40	1196.00	611.90
4	93.290	104.30	1854.00	563.60
5	55.75	125.40	1925.00	159.10
6	78.37	64.300	1071.00	583.40
10	346.40	139.80	3856.00	463.20
11	218.10	105.30	3451.00	287.80
14	369.60	226.20	804.20	466.10
15	465.00	307.30	591.20	377.80
22	194.20	169.20	651.40	277.40
23	94.22	128.40	1196.00	611.90
24	298.70	255.50	658.80	604.90
26	93.29	104.30	1854.00	563.60
27	232.80	103.90	944.50	496.20

IP = Intraperitoneal.

IV = Intravenous.

Oral = Oral.

SC = Subcutaneous.

Conclusion

Theoretical analyzes on the interaction of pyrimidinone derivatives with the 4ic2 protein surface suggest that pyrimidinone derivatives 1-6, 10, 11, 14, 15, 22-24, 26, and 27 might have a higher affinity for XIAP translated as greater XIAP inhibition compared with the controls. These data suggest that pyrimidinone derivatives could be good candidates to treat cancer through XIAP inhibition.

Acknowledgments

None.

Conflict of interest

None.

Financial support

None.

Ethics statement

This study developed out following the rules of professional ethics involved in the pharmacochemical research laboratory of the Autonomous University of Campeche.

References

1. Xia C, Dong X, Li H, Cao M, Sun D, He S, et al. Cancer statistics in China and the United States. Chinese Med J. 2022;135(05):584-90.
2. Hanahan D. Hallmarks of cancer: New dimensions. Cancer Dis. 2022;12(1):31-46.
3. Little M, Jordens F, Paul K, Montgomery K, Philipson B. Liminality: A major category of the experience of cancer illness. J Bioet Inq. 2022:19(1):37-48.
4. Brenner DR, Weir HK, Demers AA, Ellison LF, Louzado C, Shaw A, et al. Projected estimates of cancer in Canada in 2020. Canada Med Assoc. 2020;192(9):199-205.
5. Hong S, Won Y, Park Y, Jung K, Kong H, Lee E. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2017. Cancer research and treatment. J Korean Cancer Assoc. 2020;52(2):335-50.
6. Mathur P, Sathishkumar K, Chaturvedi M, Das P, Sudarshan L, Santhappa S, et al. Cancer statistics, 2020: Report from national cancer registry programme, India. JCO Global Oncol. 2020;6:106375.
7. Pucot JR, Manting MM, Demayo CG. Ethnobotanical plants used by selected indigenous peoples of Mindanao, the Philippines as cancer therapeutics. Pharmacophore. 2019;10(3):61-9.
8. Babaei H, Sepahy AA, Amini K, Saadatmand S. The effect of titanium dioxide nanoparticles synthesized by bacillus tequilensis on clb gene expression of colorectal cancer-causing Escherichia coli. Arch Pharm Pract. 2020;11(1):22-31.
9. Alhomayani FK, Althumali AM, Alhamyani A, Alsufyani AA, Alharthi NA, Almalki MS. Awareness of hemodialysis patients regarding symptoms of cancer at king Abdul-Aziz specialized hospital, Taif city. Arch Pharm Pract. 2020;11(2):69-80.
10. Uhlenhopp D, Then E, Sunkara T, Gaduputi V. Epidemiology of esophageal cancer: Update in global trends, etiology, and risk factors. Clin J Gast. 2020;13(6):1010-21.
11. Zhang S, Xu H, Zhang L, Qiao Y. Cervical cancer: Epidemiology, risk factors, and screening. Chinese J Cancer Res. 2020;32(6):720.
12. Sun D, Li H, Cao M, He S, Lei L, Peng J, et al. Cancer burden in China: Trends, risk factors, and prevention. Cancer Biol Med. 2020;17(4):879.
13. Georgakopoulos-Soares I, Chartoumpekis D, Kyriazopoulou V, Zaravinos A. EMT factors and metabolic pathways in cancer. Frontiers Oncol. 2020;10:499.
14. Saha G, Sarkar S, Mohanta P, Kumar K, Chakrabarti S, Basu M, et al. USP7 targets XIAP for cancer progression: Establishment of a p53-independent therapeutic avenue for glioma. Oncogene. 2022;41(47):5061-75.
15. Daoud M, Broxtermann P, Schorn F, Werthenbach J, Seeger J, Schiffmann L, et al. XIAP promotes melanoma growth by inducing tumour neutrophil infiltration. EMBO Rep. 2022;23(6):e53608.
16. Hanifeh M, Ataei F. XIAP as a multifaceted molecule in Cellular Signaling. Apoptosis. 2022;27(7-8):441-53.
17. Kuo YC, Yang I, Rajesh R. Suppressed XIAP and cIAP expressions in human brain cancer stem cells using BV6-and GDC0152-encapsulated nanoparticles. J Taiwan Inst Chem Eng. 2022;135:104394.
18. Cremona M, Vandenberg CJ, Farrelly AM, Madden SF, Morgan C, Kalachand R, et al. BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors. Br J Cancer. 2022;127(3):488-99.
19. Li J, Cen W, Tong C, Wang L, Zhang W, Deng S, et al. Fangchinoline induces gallbladder cancer cell apoptosis by suppressing PI3K/Akt/XIAP axis. Plos One. 2022;17(4):e0266738.
20. Yin S, Chen Y, Tong H, Li T, Qin Z, Zhu J, et al. PP2A promotes apoptosis and facilitates docetaxel sensitivity via the PP2A/p eIF4B/XIAP signaling pathway in prostate cancer. Oncol Lett. 2022;23(3):1-9.
21. Wilke N, Abodo L, Frias C, Frias J, Baas J, Jakupec M, et al. The gallium complex KP46 sensitizes resistant leukemia cells and overcomes Bcl-2-induced multidrug resistance in lymphoma cells via upregulation of Harakiri and downregulation of XIAP in vitro. Biom Pharmacother. 2022;156:113974.
22. Xu M, Zhang L, Guo Y, Bai L, Luo Y, Wang B, et al. Nanoemulsion Co-Loaded with XIAP siRNA and gambogic acid for inhalation therapy of lung cancer. Int J Mol Sci. 2022;23(22):14294.
23. Engelmann C, Schuhmachers P, Zdimerova H, Virdi S, Hauri-Hohl M, Pachlopnik- Schmid J, et al. Epstein Barr virus-mediated transformation of B cells from XIAP-deficient patients leads to increased expression of the tumor suppressor CADM1. Cell Death Dis. 2022;13(10):892.
24. Cater M, Haupt Y. Clioquinol induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP): Therapeutic indication for prostate cancer. Biochem J. 2011;436(2):481-91.
25. Sun, H, Lu J, Liu L, Yi H, Qiu S, Yang C, et al. Nonpeptidic and potent small-molecule inhibitors of cIAP-1/2 and XIAP proteins. J Med Chem. 2010;53(17):6361-7.
26. Kester R, Donnell A, Lou Y, Remiszewski S, Lombardo L, Chen S, et al. Optimization of benzodiazepinones as selective inhibitors of the X-linked inhibitor of apoptosis protein (XIAP) second baculovirus IAP repeat (BIR2) domain. J Med Chem. 2013;56(20):7788-03.
27. Nikolovska-Coleska Z, Xu L, Hu Z, Tomita Y, Li P, Roller P, et al. Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem. 2004;47(10):2430-40.
28. Peng Y, Sun H, Lu J, Liu L, Cai Q, Shen R, et al. Bivalent Smac mimetics with a diazabicyclic core as highly potent antagonists of XIAP and cIAP1/2 and novel anticancer agents. J Med Chem. 2012;55(1):106-14.
29. National Library of Medicine. National Center for Biotechnology Information. available from: https://pubchem.ncbi.nlm.nih.gov
30. Wu Z, Gu L, Zhang S, Liu T, Lukka PB, Meibohm B, et al. Discovery of N-(3, 4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2, 3, 3a, 4, 5, 9b-hexahydrofuro [3, 2-c] quinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor. J Med Chem. 2021;64(4):1930-50.
31. Danquah M, Duke C, Patil R, Miller D, Mahato R. Combination therapy of antiandrogen and XIAP inhibitor for treating advanced prostate cancer. Pharm Res. 2012;29:2079-91.
32. Polykretis P, Luchinat E, Bonucci A, Giachetti A, Graewert M, Svergun D, et al. Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach. IUCrJ. 2019;6(5):948-57.
33. Figueroa-Valverde L, Rosas-Nexticapa M, Montserrat M, Díaz-Cedillo F, López-Ramos M, Alvarez-Ramirez M, et al. Synthesis and Theoretical Interaction of 3-(2-oxabicyclo [7.4. 0] trideca-1 (13), 9, 11-trien-7-yn-12-yloxy)-steroid Derivative with 17β-hydroxysteroid Dehydrogenase Enzyme Surface. Bioint Res Appl Chem. 2023;13:266.
34. Lauro F, Marcela R, Maria L, Francisco D, Magdalena A, Virginia M, et al. Effect produced by a cyclooctyne derivative on both infarct area and left ventricular pressure via calcium channel activation. Drug Res. 2023. doi:10.1055/a-1967-2004
35. Rudik A, Dmitriev A, Lagunin A, Filimonov D, Poroikov V. Computational prediction of inhibitors and inducers of the major isoforms of cytochrome P450. Molecules. 2022;27(18):1-9.
36. Schön K, Koristkova B, Kacirova I, Brozmanova H, Grundmann M. Comparison of Mw\Pharm 3.30 and Mw\Pharm++, a Windows version of pharmacokinetic software for PK/PD monitoring of vancomycin. Part 1: A-posteriori modelling. Comp Met Prog Biom. 2022;214:106552.
37. Grassin-Delyle S, Semeraro M, Lamy E, Urien S, Runge I, Foissac F, et al. Pharmacokinetics of tranexamic acid after intravenous, intramuscular, and oral routes: a prospective, randomised, crossover trial in healthy volunteers. British J Anaest. 2022;128(3):465-72.
38. Wechalekar A, Sanchorawala V. Daratumumab in AL amyloidosis. blood. J Am Soc Hematol. 2022;140(22):2317-22.
39. Lauro F, Marcela R, Maria LR, Magdalena A, Virginia M, Francisco D, et al. Evaluation of biological activity of a diazocine derivative against heart failure using an ischemia-reperfusion injury model. Drug Res. 2022;72(07):404-11.
40. Zhu Q, Yang Y, Lao Z, Zhong Y, Zhang K, Zhao S. Acute and chronic toxicity of deltamethrin, permethrin, and dihaloacetylated heterocyclic pyrethroids in mice. Pest Manag Sci. 2020;76(12):4210-21.
41. Zhu Q, Yang Y, Lao Z, Zhong Y, Zhang K, Zhao S. Photodegradation kinetics, mechanism and aquatic toxicity of deltamethrin, permethrin and dihaloacetylated heterocyclic pyrethroids. Sci Environ. 2020;749:142106.
42. Kisielius V, Hama J, Skrbic N, Hansen H, Strobel B, Rasmussen L. The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids. Scic Rep. 2020;10(1):1-10.
43. Alimoradi S, Stohr H, Stagg-Williams S, Sturm B. Effect of temperature on toxicity and biodegradability of dissolved organic nitrogen formed during hydrothermal liquefaction of biomass. Chemos. 2020;238:124573.

Introduction

molecular mechanisms involved in cancer. Analyzing this hypothesis, the objective of this study was to evaluate the interaction of twenty-seven pyrimidinone derivatives with XIAP using a theoretical model.

Materials and Methods

1 = 1,3-Dimethyl-3,4,5,6,-tetrahydro-2(1H)-pyrimidinone

Ligand-protein evaluation

Pharmacokinetics parameter

Toxicity evaluation

The possible toxicity produced by pyrimidinone derivatives (2, 5, 9, 11, 13, and 15) was determined using the GUSAR software.[35]

Results and Discussion

Table 1. Aminoacid residues are involved in the interaction of pyrimidinone derivates with the 4ic2-protein surface

Table 2. Thermodynamic parameters involved in the interaction of pyrimidinone derivates with the 4ic2-protein surface.

Table 3. Pharmacokinetic parameters for pyrimidinone derivatives

Table 4. Theorethical toxicity produced by compouns A,B,C, and pyrimidinone derivatives (1-6, 10, 11, 14, 15 22-24 26 and 27) using the Gussar software.

Acknowledgments

Conflict of interest

Financial support

Ethics statement

The possible toxicity produced by pyrimidinone derivatives (2, 5, 9, 11, 13, and 15) was determined using the GUSAR software.^[35]