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An official publication of the Middle-Eastern Association for Cancer Research
Clinical Cancer Investigation Journal
ISSN Print: 2278-1668, Online: 2278-0513
ARTICLE
Year: 2023   |   Volume: 12   |   Issue: 2   |   Page: 27-32     View issue

Theoretical Evaluation of Twenty-Cannabinoid Derivatives on Either Androgen Receptor or 5α-Reductase Enzyme

 

Maria Lopez-Ramos1, Lauro Figueroa-Valverde1, Francisco Diaz-Cedillo2, Marcela Rosas-Nexticapa3, Magdalena Alvarez-Ramirez3

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


Abstract

There are studies which suggest that some cannabinoids derivatives can produce effects on prostate cancer; however, the effect exerted on androgen receptor and 5a-reductase is very confusing; perhaps, this phenomenon is due to differences in the chemical structure of cannabinoids. The aim of this theoretical research was to evaluate the possible interaction of twenty-cannabinoids derivatives (compounds 1 to 20) with either androgen receptor or 5a-reductase enzyme using either 3L3X or 7BW1 proteins as the theoretical models. Besides, testosterone, dihydrotestosterone, dutasteride, finasteride and flutamide drugs were used as theoretical tools. The results showed higher affinity of cannabinoid derivatives 6, 13, 16 and 20 for the androgen receptor surface compared to testosterone, dihydrotestosterone and flutamide. In addition, other data indicate that cannabinoid derivatives 1, 3, 14 and 18 could have higher affinity by 5a-reductase enzyme compared with dutasteride and finasteride. All these data suggest that cannabinoid derivatives 6, 13, 16 and 20 could act as androgen receptor inhibitors. In addition, the cannabinoid analogs 1, 3, 14 and 18 could exert their biological activity as 5a-reductase enzyme inhibitors. This phenomenon could be translated as good candidates for the treatment of prostate cancer.

Keywords: Prostate cancer, Cannabinoid, Androgen receptor, 5α-reductase


Introduction

Several Mortality rate from prostate cancer has increased in recent years worldwide.[1, 2] It is important to mention that there are several factors involved in the development of this clinical pathology such as genetics,[3] obesity,[4] aging,[5] alcohol.[6] Additionally, some studies indicate that androgens and their receptors may be associated with prostate cancer.[7, 8] It is noteworthy that currently several drugs are used to treat patients with prostate cancer, such as flutamide[9] nilutamide[10] bicalutamide[11] enzalutamide[12] and apalutamide[13] finasteride[14] and dutasteride.[15] However, some drugs can produce some secondary effects, such as hot flashes[16] hypertension[17] hepatotoxicity[18] and erectile dysfunction.[19] In the search for new alternative therapeutics for treating prostate cancer, some compounds have been prepared; for example, a study showed the synthesis of dimethylcurcumin from curcumin and diazomethane with biological activity on the androgen receptor using DU145 and PC-3 human prostate cancer cell lines.[20, 21] Besides, a report displayed the reaction of an aminobenzamide analog with cyanohydrin to form a fluorobenzamide derivative as anticancer agent using LNCaP cells line.[22, 23] Other data indicate that JNJ-63576253 drug could be a therapeutic alternative for the treatment of patients with prostate cancer who do not respond to enzalutamide and apalutamide.[24, 25] In addition, a phenoxybenzoylphenyl acetic acid derivative was prepared as 5α-reductase enzyme inhibitor using either rat prostate homogenates or human prostate homogenate.[26] Recently, a study showed the interaction of some dibenzo derivatives on both androgen receptor and 5α-reductase enzyme using a theoretical model.[27]

On the other hand, some studies suggest that cannabinoid derivatives may reduce prostate cancer.[28, 29] For example, one study showed that a cannabinoid derivative WIN-55,212-2) produces decreased growth of LNCaP cells (androgen-sensitive human prostate cells).[30] In addition, one study indicates that the cannabinoid derivative chromenopyrazoldione may decrease the LNCaP cells growth.[31]

Other data showed that (R)-methanandamide drug (a cannabinoid
 

 

derivative) could modify the expression of the androgen receptor in an androgen-dependent cell line, resulting in the regulation of prostate cell growth.[32] However, a study displayed that both (R)-methanandamide and WH-015 drug decreasing prostate cancer though CB2 cannabinoid-receptor using a PC-3 cell line (human prostate epithelial cells).[33] All this data suggests that some cannabinoid derivatives can produce effects on prostate cancer; however, the possible effect exerted on either androgen receptor, or 5-a reductase enzyme is very confusing; perhaps, this phenomenon is due to differences in the chemical structure of cannabinoids. Analyzing this hypothesis. The aim of this theoretical study was to evaluate the possible interaction of twenty-cannabinoids derivatives on either androgen receptor or 5a-reductase enzyme using testosterone, dihydrotestosterone, flutamide, dutasteride, and finasteride drugs as theoretical tools in a Docking model.

Materials and Methods

Twenty-cannabinoid derivatives were used as theoretical tools (Figure 1) to evaluate their possible interaction with either androgen receptor or 5a-reductase enzyme as follows:

Figure 1. Chemical structure of cannabinoid derivatives (1-27). Source: ChemPub (https://pubchem.ncbi.nlm.nih.gov/).

1 = Cannabigerol

2 = Cannabigerol monomethyl ether

3 = Cannabinerolic acid

4 = Cannabigerovarin

5 = Cannabigerolic acid

6 = Cannabigerovarinic acid

7 = Cannabichromene

8 = Cannabichromenic acid

9 = Cannabivarichromene

10 = Cannabichromevarinic acid

11 = Cannabidiol CBD-C5

12 = Cannabidiol monomethyl ether

13 = Cannabidiol

14 = Cannabidivarin

15 = Cannabidiorcol

16 = Cannabidiolic acid

17 = Cannabidivarinic acid

18 = Cannabinodiol

19 = Cannabinodivarin

20 = Dronabinol

Ligand-protein complex

The interaction of opioid derivatives with either androgen receptor or 5a-reductase enzyme surface was evaluated using either 3L3X (PDB DOI: 10.2210/pdb3L3X/pdb)[34] or 7BW1 (PDB DOI: 10.2210/pdb7BW1/pdb)[35] proteins as theoretical models. Besides, to evaluate the different types of binding energy involved in opioid derivative-protein complex formation, the DockingServer program was used.[36]

Pharmacokinetics parameter

Some Pharmacokinetic involved in the chemical structure of cannabinoid derivatives (1, 3, 6, 13, 16, 18 and 20) were determined using the SwissADME software.[37]

Toxicity analysis

Theorethical toxicity produced by either cannabinoid derivatives (1, 3, 6, 13, 14, 16, 18 and 20) was determined using GUSAR software.[38]

Results and Discussion

Protein-ligand analysis

Several methods to predict the interaction of several drugs with androgen receptor such as Gold,[39] Glide,[40] Autodock,[41] and DockigServer[42] have reported. For example, a theoretical study indicates that hormone-binding site which is well-characterized as a hydrophobic cavity that forms strong hydrophobic interactions with a steroidal core of androgens.[43] Another report showed that amino acid residues such as Asn705 and Thr877 may involve hydrogen bond interactions with the 17-hydroxy group of testosterone and Gln711 and Arg752 with the 3-keto group of this androgen.[44] In addition, a theoretical study suggests that some cannabinoids such as tetrahydrocannabinol and cannabidiol may have biological activity on androgen receptor translated as an inhibition of prostate cancer progression.[45] Analyzing these data, and other studies which suggest that cannabinoids may reduce prostate cancer;[28, 30-33] in this investigation twenty cannabinoid derivatives were used to evaluate their interaction with androgen receptor using at 3L3X protein as theoretical model. The results (Table 1) showed that interaction of cannabinoid derivatives with 3L3X protein surface could possibly involve some different aminoacid-residues compared to testosterone, dihydrotestosterone and flutamide.

 

Table 1. Aminoacid residues involved in the coupling cannabinoides derivatives (compounds 1-20) with 3L3X protein surface

Compound

Aminoacid residues

Flutamide

Leu701; Leu704; Leu707; Gln711; Met742; Met745; Val746; Met749; Arg752; Phe764; Met787; Leu873; Thr877

Testosterone

Leu701; Leu704; Asn705; Gln711; Trp741; Met742; Met745; Val746; Met749; Arg752; Phe764; Met780; Met787; Leu873; Thr877; Met895

DHT

Leu701; Leu704; Asn705; Gln711; Met742; Met745; Met749; Arg752; Phe764; Met780; Leu873; Phe876; Thr877; Leu880; Met895

1

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Arg752; Phe764; Met780; Met787; Leu873; Thr877; Met895

2

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Arg752; Phe764; Met780; Met787; Leu873; Thr877

3

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Arg752; Phe764; Met780; Met787; Leu873; Phe876; Thr877; Met895

4

Leu701; Leu707; Gln711; Trp741; Met742; Met745; Val746; Phe764; Met780; Met787; Leu873; Phe876; Thr877; Met895

5

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Arg752; Phe764; Met780; Leu873; Thr877; Met895

6

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Phe764; Met780; Met787; Leu873; Phe876; Thr877; Met895

7

Leu704; Leu707; Gln711; Met742; Met745; Val746; Met749; Arg752; Phe764; Met780; Leu873; Phe876; Thr877; Met895

8

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Phe764; Met780; Met787; Thr877; Met895

9

Leu704; Asn705; Trp741; Met742; Met745; Val746; Met749; Phe764; Met787; Leu873; Thr877; Met895

10

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Arg752; Phe764; Met780; Met787; Leu873; Thr877; Met895

11

Leu701; Leu704; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Phe764; Met780; Met787; Leu873; Phe876; Thr877

12

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Arg752; Phe764; Met780; Thr877; Met895; Ile899

13

Leu701; Leu704; Asn705; Leu707; Gln711; Met745; Val746; Met749; Phe764; Met780; Met787; Leu873; Phe876; Thr877; Met895

14

Leu701; Leu704; Leu707; Gln711; Met742; Met745; Val746; Met749; Phe764; Met780; Met787; Leu873; Phe876; Thr877

15

Leu701; Leu704; Asn705; Leu707; Trp741; Met742; Met745; Val746; Phe764; Leu873; Phe876; Thr877; Met895

16

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Phe764; Met780; Met787; Leu873; Phe876; Thr877

17

Leu701; Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Phe764; Met780; Met787; Leu873; Phe876; Thr877; Met895

18

Leu704; Asn705; Leu707; Gln711; Met749; Phe764; Met780; Leu873; Met895

19

Leu704; Asn705; Leu707; Gln711; Trp741; Met742; Met745; Val746; Met749; Arg752; Phe764; Met780; Met787; Leu873; Phe876; Thr877; Met895

20

Leu704; Leu707; Gln711; Trp741; Met745; Val746; Met749; Arg752; Phe764; Met780; Met787; Leu873; Phe876; Thr877; Met895

However, it is important to mention that a study showed that some thermodynamic parameters are involved in the interaction of testosterone and its analogues on the androgen receptor.[46] For this reason, in this study several energy parameters (Table 2) for cannabinoid derivatives, testosterone, dihydrotestosterone and flutamide were evaluated using DockingServer program.

Table 2. Thermodynamic parameters involved in the interaction of cannabinoid derivates with the 3L3X-protein surface

Comp

I

II

II

IV

V

VI

Flu

-7.3

3.9

-8.5

0.0

-8.5

456.0

Test

-7.7

26.3

-10.4

-0.1

-10.6

499.3

DHT

-10.7

13.3

-10.9

-0.1

-11.0

490.5

1

-7.2

4.6

-10.0

0.0

-10.0

552.3

2

-5.8

50.5

-8.6

0.0

-8.5

553.4

3

-5.5

91.3

-7.8

-0.1

-7.9

599.1

4

-6.7

12.3

-8.6

0.0

-8.6

523.5

5

-7.3

4.4

-9.9

0.0

-10.0

550.1

6

-7.9

1.5

-9.8

0.0

-9.8

531.6

7

-8.4

657.1

-10.2

0.0

-10.3

560.0

8

-5.9

40.6

-6.8

-0.2

-7.0

550.9

9

-7.1

5.5

-8.4

0.0

-8.4

502.0

10

-8.8

312.9

-9.1

-0.4

-9.5

515.6

11

-6.5

16.2

-9.2

0.0

-9.2

566.0

12

-7.0

6.4

-9.2

0.0

-9.2

567.3

13

-7.9

1.4

-9.9

0.0

-10.0

561.6

14

-7.2

4.9

-9.1

0.0

-9.1

538.7

15

-7.2

4.7

-8.4

0.0

-8.4

506.2

16

-7.7

1.9

-9.7

0.0

-9.8

567.6

17

-7.2

5.3

-8.4

0.0

-8.4

573.7

18

-5.1

180.1

-6.6

0.0

-6.7

434.6

19

-6.7

10.7

-8.7

0.0

-8.7

538.7

20

-7.6

2.6

-8.7

0.0

-8.7

554.5

Flu = Flutamide

Test = Testosterone

DHT = Dihydrotestosterone

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

The results showed differences in bond-energy levels for cannabinoid derivatives, testosterone, dihydrotestosterone and flutamide. Besides, the inhibition constant (Ki) was lower for cannabinoid derivatives 6, 13, 16 and 20 compared to testosterone dihydrotestosterone and flutamide; these data suggest that these cannabinoid analogues could act as androgen receptor inhibitors, resulting in a decrease in prostate cancer. However, it is noteworthy that other molecular mechanisms are involved in the development of prostate cancer; for example, several studies indicate that some drugs such as dutasteride and finasteride (5a-reductase enzyme inhibitors)[14, 47] can decrease prostate cancer. Analyzing these data, the aim of this research was to evaluate the theoretical interaction of cannabinoid derivatives (Compound 1 to 20) on 5a-reductase enzyme using at 7BW1 protein, dutasteride and finasteride as theoretical tools (Table 3)

Table 3. Aminoacid residues involved in the coupling cannabinoides derivatives (compounds 1-20) with 7BW1 protein surface

Compound

Aminoacid residues

Flut

Ile202; Ala205; Leu206; Trp209; Leu211; Leu214; Ala217; Phe218

Test

Tyr129; Ala134; Glu135; Tyr136; Thr208; Trp209; Ser210; Leu211

1

Ile202; Ala205; Leu206; Trp209; Leu211; Leu214

2

Ile202; Ala205; Leu206; Trp209; Leu214

3

Leu206; Trp209; Leu214

4

Tyr129; Ile202; Ala205; Trp209; Leu211; Leu214

5

Tyr129; Ala205; Leu206; Trp209; Leu211; Leu214

6

Ile202; Leu206; Trp209; Leu214; Phe218; Leu221

7

Tyr129; Ile202; Ala205; Prt209; Leu211; Leu214

8

Ile202; Ala205; Leu206; Trp209; Leu214

9

Ile144; Arg145; Leu148; Ile202; Ala205; Leu206; Trp209; Leu214

10

Tyr129; Ala205; Trp209; Ser210; Leu211; Leu214

11

Ile202; Ala205; Leu206; Trp209; Leu214

12

Ile202; Ala205;Trp209; Leu211; Leu214; Ala217

13

Ile202; Ala205; Leu206; Trp209; Leu211; Leu214

14

Tyr129; Ala205; Leu206; Trp209;Leu211; Leu214

15

Ile202; Ala205; Leu206; Trp209; Leu214

16

Ala205; Leu206; Trp209; Leu211; Leu214

17

Ile202; Ala205; Leu206; Leu214; Ala217; Phe218; Leu221

18

Ala205; Leu206; Trp209; Leu211; Leu214

19

Ile202; Ala205; Leu206; Leu214; Ala217

20

Ile202; Ala205; Leu206; Trp209; Leu214; Ala217; Ala218

Flu = Flutamide

Test = testosterone

The results showed differences in some aminoacid residues for cannabinoid derivatives compared with dutasteride and finasteride. Besides, the Ki for cannabinoid analogs such as 1, 3, 14 and 18 was lower compared with dutasteride and finasteride (Table 4); These data suggest that these cannabinoid derivatives could act as 5a-reductase enzyme inhibitors, producing a decrease in prostate cancer.

Table 4. Thermodynamic parameters involved in the interaction of cannabinoid derivates with the 7BW1-protein surface.

Comp

I

II

II

IV

V

VI

Dut

-8.8

326.1

-9.3

0.0

-9.3

683.7

Finast

-6.7

12.3

-6.8

0.0

-6.8

619.7

1

-3.8

1.4

-6.7

0.0

-6.7

669.1

2

-4.9

229.5

-7.6

0.0

-7.7

651.2

3

-3.7

1.6

-5.8

-0.1

-5.9

628.5

4

-4.6

421.6

-7.2

0.0

-7.3

655.4

5

-5.03

205.92

-7.55

-0.16

-7.70

694.37

6

-4.3

699.1

-6.2

0.0

-6.3

570.1

7

-4.6

382.7

-5.8

0.0

-5.8

538.7

8

-5.8

51.2

-7.3

0.1

-7.4

715.9

9

-5.4

109.5

-7.0

0.0

-7.0

640.9

10

-5.3

114.5

-6.7

0.0

-6.7

617.1

11

-4.8

263.5

-7.1

0.0

-7.1

642.4

12

-4.8

269.8

-7.1

+0.0

-7.1

619.2

13

-4.8

277.1

-6.7

0.0

-6.8

576.2

14

-4.0

1.0

-5.8

0.0

-5.8

582.7

15

-4.7

312.9

-5.9

0.0

-5.9

529.1

16

-4.5

484.7

-6.6

0.0

-6.6

644.3

17

-5.7

61.7

-6.8

-0.1

-6.9

566.0

18

-3.7

1.9

-5.3

0.0

-5.3

496.4

19

-4.2

823.8

-5.9

0.0

-5.9

572.3

20

-5.2

132.2

-6.6

0.0

-6.66

626.9

Com = Compound

Dut = Dutasteride

Finast = Finasteride

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

Pharmacokinetic characteristics is an area which have been focused on quantitative pharmacological studies for anticancer drugs.[48] It is important to mention that several theoretical methods have been used to predict some pharmacokinetic parameters, such as PKQuest[49] PharmPK,[50] and SwissADME.[51] Analyzing these data, in this investigation, some pharmacokinetic parameters for cannabinoid derivatives 1, 3, 6, 13, 14, 16, 18 and 20 were evaluated using the SwissADME program. Theoretical results (Table 5) show differences in gastrointestinal absorption and metabolism involving some cytochrome P450 systems; this phenomenon could depend on the chemical structure of the cannabinoid derivatives and their degree of lipophilicity.

Table 5. Pharmacokinetic parameters for cannabinoid derivatives

Com

i

ii

iii

iv

v

vi

vii

viii

 

Flu

High

Yes

No

Yes

Yes

No

No

No

 

Test

High

Yes

Yes

No

No

No

No

No

 

DHT

High

Yes

No

No

No

No

No

No

 

Dut

Low

Yes

No

No

No

No

No

Yes

 

Finast

High

Yes

Yes

No

No

No

No

No

 

1

High

No

No

Yes

Yes

No

Yes

No

 

3

High

No

No

Yes

No

Yes

No

No

 

6

High

Yes

No

Yes

No

Yes

No

Yes

 

13

High

Yes

No

No

Yes

Yes

No

Yes

 

14

High

Yes

No

No

Yes

Yes

No

Yes

 

16

High

Yes

No

No

Yes

Yes

Yes

Yes

 

18

High

No

Yes

Yes

Yes

Yes

Yes

No

 

20

High

No

No

No

No

No

No

No

 

Com = Compound

Flu = Flutamide

Test = Testosterone

DHT = Dihydrotestosterone

Dut = Dutasteride

Finast = Finasteride

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 PO/W

Toxicity analysis

Some methods have been used to predict the degree of toxicity of various compounds such as ADME/Tox,[52] eToxPred,[53] GUSSAR.[54] Analyzing these data, the aim of this study was to evaluate the possible toxic effect produced by cannabinoid derivatives 1, 3, 6, 13, 14, 16, 18 and 20 using the GUSSAR software. The results (Table 6) suggest that lower doses of cannabinoid derivatives are needed (via oral) to produce toxicity compared to testosterone and dihydrotestosterone. Besides, other data indicate that compounds 13, 14, 16 and 20 require low doses to induce toxicity compared with dutasteride and finasteride.

Table 6. Pharmacokinetic parameters for cannabinoid derivatives

Com

IP LD50 (mg/kg)

IV LD50 (mg/kg)

Oral LD50 (mg/kg)

SC LD50 (mg/kg)

Test

1163.00

24.99

2244.00

2324.00

DHT

1221.00

34.50

2642.00

2069.00

Flut

479.70

156.70

387,10

430.70

Dut

254.10

37.36

946.70

1360.00

Finast

947.80

30.75

1816.00

2268.00

1

582.50

91.93

2813.00

1108.00

3

400.90

142.60

1530.00

561.50

6

469.00

206.30

2346.00

664.10

13

343.300

38.530

799.20

17450

14

365.10

40.55

710,500,

99,420

16

296.30

63.87

786.40

174.60

18

698.70

53.30

1985.00

607.90

20

395.90

39.85

745.50

50.41

Com = Compound

Flu = Flutamide

Test = Testosterone

DHT = Dihydrotestosterone

Dut = Dutasteride

Finast = Finasteride

IP = Intraperitoneal.

IV = Intravenous.

Oral = Oral.

 SC = Subcutaneous.

Conclusion

In this investigation, the theoretical interaction of twenty cannabinoid derivatives with the androgen receptor or 5α-reductase enzyme was determined. Theoretical interaction showed higher affinity of cannabinoid derivatives 6, 13, 16 and 20 for the androgen receptor surface compared to testosterone, dihydrotestosterone and flutamide. Besides, other results suggest that cannabinoid derivatives 1, 3, 14 and 18 could have higher affinity by 5a-reductase enzyme compared with dutasteride and finasteride. All these data suggest that cannabinoid derivatives 6, 13, 16 and 20 could act as androgen receptor inhibitors. In addition, the cannabinoid analogs 1, 3, 14 and 18 could exert their biological activity as 5a-reductase enzyme inhibitors. This phenomenon could be translated as good candidates for the treatment of breast cancer.

Acknowledgments

None.

Conflict of interest

None.

Financial support

None.

Ethics statement

None.

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