30DEC

Libyan International Conference for Health Sciences

The First Libyan International Conference for Health Sciences (2024): Open University, Tripoli, Libya
Mediterranean Journal of Pharmacy and Pharmaceutical Sciences
https://ppj.org.ly/article/doi/10.5281/zenodo.14293578

Mediterranean Journal of Pharmacy and Pharmaceutical Sciences

Review

Insight into the synthesis of warfarin and its promiscuous derivatives

Marwa Ghouizi, Khaled Sekkoum, Nasser Belboukhari

http://dx.doi.org/10.5281/zenodo.14293578 Mediterr J Pharm Pharm Sci, Ahead of Print, 2024
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Abstract

Warfarin is the most widely used anticoagulant drug which reduces the risk of blood clots forming. This review aims to highlight the significant research on the synthesis of warfarin and its derivatives using numerous methods such as Michael reactions, green enantioselective, one-pot condensation, and catalytic synthesis. The synthesis of warfarin derivatives was discussed since they have proven to have higher biological activity than warfarin itself. Further, this review was carried out to figure out the shortcomings in the synthesis methods and shed light on the contribution of each research on the development and design of stereospecific synthesis of warfarin or its derivatives which were proven to be potent hits with an acceptable cost. Moreover, the contribution of some methods in green chemistry advancement has been investigated.

Keywords

Amines, catalysts, green synthesis, microwave, on water synthesis

References

  1. Chen X, Kang Y, Zeng S (2018) Analysis of stereoisomers of chiral drug by mass spectrometry. Chirality. 30 (5): 609-618. doi: 10.1002/chir.22833
  2. Kessler CM (2006) Urgent reversal of warfarin with prothrombin complex concentrate: where are the evidence‐based data? Journal of Thrombosis and Haemostasis. 4 (5): 963-966. doi: 10.1111/j.1538-7836.2006.01944.x
  3. Porter WR (2010) Warfarin: history, tautomerism and activity. Journal of Computer-Aided Molecular Design. 24 (6): 553-573. doi: 10.1007/s10822-010-9335-7
  4. Aleksandrov AP, Belij-Rammerstorfer S, Mirkov I, Subota V, Kulas J, Kataranovski D, Kataranovski M (2018) Oral warfarin affects some aspects of systemic immunomodulation with topical dinitrochlorobenzene (DNCB) in rats. Cutaneous and Ocular Toxicology. 37 (1): 29-35. doi: 10.1080/15569527.2017.1328690
  5. AL-Ameen TM, Al-Metwali BZ (2024) Comparison of quality of life and treatment satisfaction among sample of Iraqi patients using anticoagulant therapy (warfarin or non-vitamin k antagonist oral anticoagulants). Journal of the Faculty of Medicine Baghdad. 66 (3): 268-275. doi: 10.32007/jfacmedbaghdad.6632262
  6. Parekh S, Xu L, Livingstone C (2024) An evaluation of oral anticoagulant safety indicators by England’s Community Pharmacies. Pharmacy. 12 (5): 134. doi: 10.3390/pharmacy12050134
  7. Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Annals of Internal Medicine. 146 (12): 857-867. doi: 10.7326/0003-4819-146-12-200706190-00007
  8. Turpie AG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kälebo P, Misselwitz F, Gent M; OdiXa-Knee Study Group (2005) BAY 59‐7939: An oral, direct factor Xa inhibitor for the prevention of venous thrombo-embolism in patients after total knee replacement. A phase II dose‐ranging study. Journal of Thrombosis and Haemostasis. 3 (11): 2479-2486. doi: 10.1111/j.1538-7836.2005.01602.x
  9. Milentijevic D, Lin JH, Connolly N, Chen YW, Kogan E, Shrivastava S, Sjoeland E, Alberts MJ (2021) Risk of stroke outcomes in atrial fibrillation patients treated with rivaroxaban and warfarin. Journal of Stroke and Cerebrovascular Diseases. 30 (5): 105715. doi: 10.1016/j.jstrokecerebrovasdis.2021.105715
  10. Bembenek J, Karlinski M, Kobayashi A, Czlonkowska A (2011) Early stroke-related deep venous thrombosis: Risk factors and influence on outcome. Journal of Thrombosis and Thrombolysis. 32 (1): 96-102. doi: 10.1007 /s11239-010-0548-3
  11. Soroceanu A, Burton DC, Oren JH, Smith JS, Hostin R, Shaffrey CI, Akbarnia BA, Ames CP, Errico TJ, Bess S, Gupta MC, Deviren V, Schwab FJ, Lafage V: International Spine Study Group (2016) Medical complications after adult spinal deformity surgery: Incidence, risk factors, and clinical impact. Spine. 41 (22): 1718-1723. doi: 10.1097/BRS.0000000000001636
  12. Omidi F, Sadeghi S, Rahmannia M, Bonjar AHS, Bonjar ASH Berger NA, Nasiri MJ (2024) Direct oral anticoagulants and cancer-related venous thromboembolism: insights from an updated meta-analysis. Current Cancer Therapy Reviews. 21. doi: 10.2174/011573394722285241004075557
  13. Zhou HQ, Zhang YK, Hu ST, Hu ST, Jiang C, Zhang JK, Wu X, Liu X, Liu T, Chen KY (2024) Application of anticoagulants in the perioperative period of PCI for patients with a history of atrial fibrillation and NSTEMI: a real-world, large multicenter retrospective clinical study. European Heart Journal. 45 (S1): ehae666-1692. doi: 10.1093/eurheartj/ehae666.1692
  14. Srivastava A, Hudson M, Hamoud I, Cavalcante J, Pai C, Kaatz S (2008) Examining warfarin underutilization rates in patients with atrial fibrillation: Detailed chart review essential to capture contraindications to warfarin therapy. Thrombosis Journal. 6 (6): 1-6.  doi: 10.1186/1477-9560-6-6
  15. Wells PS, Holbrook AM, Crowther NR, Hirsh J (1994) Interactions of warfarin with drugs and food. Annals of Internal Medicine. 121 (9): 676-683. doi: 10.7326/0003-4819-121-9-199411010-00009
  16. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Robinson E, Fullerton J (2023) Rang & Dale's Pharmacology. 10th Ed., Elsevier, USA. ISBN: 9780323873963.
  17. Robinson DS, Benjamin DM, McCormack JJ (1971) Interaction of warfarin and nonsystemic gastrointestinal drugs. Clinical Pharmacology and Therapeutics. 12 (3): 491-495. doi: 10.1002/cpt1971123491
  18. Horlocker TT, Vandermeuelen E, Kopp SL, Gogarten W, Leffert LR, Benzon HT (2010) Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines. Regional Anesthesia and Pain Medicine. 35 (1): 64-101. doi: 10.1097/AAP.0000000000000807
  19. Grandone E, Mastroianno M, Pacilli G, Colaizzo D, Margaglione A, Bikdeli B, Piazza G (2024) Blood loss in women of childbearing potential taking oral anticoagulants for venous thromboembolism (The BLEED Study). Thrombosis and Haemostasis. Preprint: 21-11-2024. doi: 10.1055/a-2461-6822
  20. Keskin Z, Gedikli MA (2024) Determination of the percentage of patients using warfarin to reach target INR. Cumhuriyet Medical Journal. 46 (1): 41-44. doi: 10.7197/cmj.1415665
  21. Ning W, Wang S, Tang H, Wu S, Huang X, Liu B, Mao Y (2024) Effect of different oral anticoagulants on cognitive function in patients with atrial fibrillation: A Bayesian network meta-analysis. Medicine. 103 (17): e37750. doi: 10.1097/MD.0000000000037750
  22. Schaefer JK, Errickson J, Kong X, Ali MA, Chipalkatti N, Haymart B, Kaatz S, Krol GD, Sood SL, Froehlich J, Barnes GD (2023) A comparison of bleeding events among patients on apixaban, rivaroxaban, and warfarin for atrial fibrillation and/or venous thromboembolism. Blood. 142 (1): 135. doi: 10.1182/blood-2023-184457
  23. Tran HA, Chunilal SD, Harper PL, Tran H, Wood EM, Gallus A (2013) An update of consensus guidelines for warfarin reversal. Medical Journal of Australia. 198 (4): 198-199. doi: 10.5694/mja12.10614
  24. Fusaro M, Dalle Carbonare L, Dusso A, Arcidiacono MV, Valenti MT, Aghi A, Pasho S, Gallieni M (2015) Differential effects of dabigatran and warfarin on bone volume and structure in rats with normal renal function. PLoS One. 10 (8): e0133847. doi: 10.1371/journal.pone.0133847
  25. Juurlink DN (2007) Drug interactions with warfarin: what clinicians need to know. Canadian Medical Association Journal. 177 (4): 369-371. doi: 10.1503/cmaj.070946
  26. Kraimi A, Belboukhari N, Sekkoum K, Aboul-Enein HY (2021) Chiral anticoagulants drugs based on coumarin. Aditum Journal of Clinical and Biomedical Research. 2 (1): 1-13. doi: 04.2021/1.1027
  27. Robinson A, Li H-Y, Feaster J (1996) The first practical asymmetric synthesis of R and S-warfarin. Tetrahedron Letters. 37 (46): 8321-8324. doi: 10.1016/0040-4039(96)01796-0
  28. Ariëns EJ, Soudijn W, Timmermans PBMWM (1983) Stereochemistry and biological activity of drugs. Blackwell Scientific Publications Oxford. Boston, USA. ISBN: 0632011556.
  29. Kaminsky LS, Guengerich FP, Dannan GA, Aust SD. Comparisons of warfarin metabolism by liver microsomes of rats treated with a series of polybrominated biphenyl congeners and by the component-purified cytochrome P-450 isozymes. Arch Biochem Biophys. 1983 225 (1): 398-404. doi: 10.1016/0003-9861(83)90045-0
  30. von Matt P, Pfaltz A (1991) Enantioselective conjugate reduction of α, β-unsaturated carboxamides with semicorrin cobalt catalysts. Tetrahedron: Asymmetry. 2 (7): 691-700. doi: 10.1016/S0957-4166(00)86123-6
  31. Halland N, Hansen T, Jørgensen KA (2003) Organocatalytic asymmetric Michael reaction of cyclic 1, 3‐dicarbonyl compounds and α, Β‐unsaturated ketones-a highly atom‐economic catalytic one‐step formation of optically active warfarin anticoagulant. Angewandte Chemie. 115 (40): 5105-5107. doi: 10.1002/anie. 200352136
  32. Li Ma-L, Yu J-H, Zhu S-F, Zhou Q-L (2019) Highly enantioselective carbene insertion into N-H bonds of aliphatic amines. Science. 366 (6468): 990-994. doi: 10.1126/science.aaw9939
  33. Dong J, Du D-M (2012) Highly enantioselective synthesis of warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalysts. Organic and Biomolecular Chemistry. 10 (40): 8125-8131. doi: 10.1039/c2ob26334c
  34. Zacchigna M, Di Luca G, Cateni F, Maurich V (2004) Improvement of warfarin biopharmaceutics by conjugation with poly (Ethylene glycol). European Journal of Pharmaceutical Sciences. 23 (4-5): 379-384. doi: 10.1016/j.ejps.2004.09.001
  35. Gebauer M (2007) Synthesis and structure-activity relationships of novel warfarin derivatives. 15 (6): 2414-2420. doi: 10.1016/j.bmc.2007.01.014
  36. Talhi O, Fernandes JA, Pinto DCGA, Almeida Paz FA, Silva AMS (2015 ) Organobase catalyzed 1, 4-conjugate addition of 4-Hydroxycoumarin on chalcones: Synthesis, NMR and Single-Crystal X-ray diffraction studies of novel warfarin analogues. Journal of Molecular Structure. 1094: 13-21. doi: 10.1016/j.molstruc.2015.03.069
  37. Kubo A, Kimachi T, Haginaka J (2021) Enantioseparation of warfarin derivatives on molecularly imprinted polymers for (S)-and (R)-Chlorowarfarin. Journal of Chromatography. A. 1641: 461995. doi: 10.1016/j.chroma. 2021.461995
  38. Sonsona IG, Marqués-López E, Gimeno MC, Herrera RP (2019) First aromatic amine organocatalysed activation of α, β-unsaturated ketones. New Journal of Chemistry. 43 (31): 12233-12240. doi: 10.1039/ C9NJ02392E
  39. Wong TC, Sultana CM, Vosburg DA (2010) A green, enantioselective synthesis of warfarin for the undergraduate organic laboratory. Journal of Chemical Education. 87 (2): 194-195. doi: 10.1021/ed800040m
  40. Kim H, Yen C, Preston P, Chin J (2006) Substrate-directed stereoselectivity in vicinal diamine-catalyzed synthesis of warfarin. Organic Letters. 8 (23): 5239-5242. doi: 10.1021/ol062000v
  41. Kucherenko AS,  Kostenko AA, Zhdankina GM, Kuznetsova OY, Zlotin SG (2018) Green asymmetric synthesis of warfarin and coumachlor in pure water catalyzed by quinoline-derived 1, 2-diamines. Green Chemistry. 20 (3): 754-759. doi: 10.1039/C7GC03626
  42. Malerich JP, Hagihara K, Rawal VH (2008) Chiral squaramide derivatives are excellent hydrogen bond donor catalysts. Journal of the American Chemical Society. 130 (44): 14416-14417. doi: 10.1021/ja805693p
  43. Yang W, Du D-M (2010) Highly enantioselective Michael addition of nitroalkanes to chalcones using chiral squaramides as hydrogen bonding organocatalysts. Organic Letters. 12 (23): 5450-5453. doi: 10.1021/ol102 294g
  44. Albrecht Ł, Dickmeiss G, Cruz Acosta F, Rodríguez-Escrich C, Davis RL, Jørgensen K (2012) Asymmetric organocatalytic formal [2+ 2]-Cycloadditions via bifunctional H-bond directing dienamine catalysis. Journal of the American Chemical Society. 134 (5): 2543-2546. doi: 10.1021/ja211878x
  45. Kochetkov SV, Kucherenko AS, Zlotin SG (2018) Asymmetric synthesis of warfarin and its analogs catalyzed by C 2-symmetric squaramide-based primary diamines. Organic & Biomolecular Chemistry. 16 (35): 6423-6429. doi: 10.1039/c8ob01576g
  46. Viktória M, Veverková E, Mečiarová M, Šebesta R (2018) Bifunctional amine-squaramides as organocatalysts in Michael/Hemiketalization reactions of β, γ-unsaturated α-ketoesters and α, β-unsaturated ketones with 4-hydroxycoumarins. The Journal of Organic Chemistry. 83 (21): 13111-13120. doi: 10.1021/acs.joc.8b01847
  47. Demir AS, Tanyel C, Gülbeyaz V, Akgün H (1996) Enantioselective synthesis of 4-hydroxy-3-(3-oxo-1-Phenyl butyl)-2H-1-benzopyran-2-one (warfarin). Turkish Journal of Chemistry. 20 (2): 139-145. doi: Nil.
  48. Cravotto G, Nano GM, Palmisano G, Tagliapietra S (2001) An asymmetric approach to coumarin anticoagulants via hetero-diels-alder cycloaddition. Tetrahedron: Asymmetry. 12 (5): 707-709. doi: 10.1016/S0957-4166(01) 00124-0
  49. Halland N, Rita RG, Jørgensen KA (2002) Organocatalytic asymmetric conjugate addition of nitroalkanes to α, β-unsaturated Enones using novel imidazoline catalysts. The Journal of Organic Chemistry. 67 (24): 8331-8338. doi: 10.1021/jo0261449
  50. Li L, Xu L-W, Ju DY, Lai GQ (2009) Asymmetric direct Aldol reactions catalyzed by a simple chiral primary diamine–Br⊘nsted acid catalyst in/on water. Synthetic Communications. 39 (5): 764-774. doi: 10.1080/ 003979 10802431131
  51. Bin T, Zhang X, Chua PJ, Zhong G (2009) Recyclable organocatalysis: highly enantioselective Michael addition of 1, 3-Diaryl-1, 3-propanedione to nitroolefins. Chemical Communications. 7: 779-781. doi: 10.1039/B813 915F
  52. Fenton RR, Stephens FS, Vagg RS, Williams PA (1995) Chiral metal complexes 44. enantiomeric discrimination in ternary cobalt (iii) complexes of N, N′-dimethyl-N, N′-Di (2-Picolyl)-1S, 2S-diaminocyclohexane and α-amino acids; Including the crystal structure of the S-prolinato complex. Inorganica Chimica Acta. 236 (1-2): 109-115. doi: 10.1016/0020-1693(95)04625-J
  53. Xie JW, Chen W, Li R, Zeng M, Du W, Yue L, Chen YC, Wu Y, Zhu J, Deng JG (2007) Highly asymmetric Michael addition to α, Β‐unsaturated ketones catalyzed by 9‐amino‐9‐deoxyepiquinine. Angewandte Chemie. 64 (3): 389-392. doi: 10.1002/anie.200603612
  54. Kristensen TE, Vestli K, Hansen FK, Hansen T (2009) New phenylglycine‐derived primary amine organo-catalysts for the preparation of optically active warfarin. European Journal of Organic Chemistry. 2009 (30): 5185-5191. doi: 10.1002/ejoc.200900664
  55. Işık M, Akkoca HU, Akhmedov IM, Tanyeli C (2016) A bis-Lewis basic 2-amino DMAP/prolinamide organo-catalyst for application to the enantioselective synthesis of warfarin and derivatives. Tetrahedron: Asymmetry. 27 (9-10): 384-388. doi: 10.1016/j.tetasy.2016.04.001
  56. Yang P, Yan H, Mao S, Russo R, Johnson J, Saykally R, Morris N (2002) Controlled growth of ZnO nanowires and their optical properties. Advanced Functional Materials. 12 (5): 323-331. doi: 10.1002/1616-3028 (20020 517)12:53.0.CO;2-G
  57. Khodabakhshi S, Karami B, Eskandaric K (2014) One-pot synthesis of novel pyrano-fused coumarins catalyzed by zinc oxide nanoparticles. Heterocycles. 89 (7): 1670-1677. doi: 10.3987/COM-14-13006
  58. Jafari F, Kodabakhshi S, Shirazi SG (2014) Zinc oxide nanorods: A new application as a powerful catalyst for the green one-pot synthesis of new warfarin analogs. RSC Advances. 4 (89): 48095-48100. doi: 10.1039/ C4RA06669C
  59. Krstic L, Slobodan S, Slavica S-S (2002) An efficient synthesis of warfarin acetals on montmorillonite clay K-10 with mictowaves. Jourenal of the Serbian Chemical Society. 67 (5): 325-329. doi: 10.2298/JSC0205325K
  60. Berlan J, Giboreau P, Lefeuvre S, Marchand C (1991) Synthese organique sous champ microondes: Premier exemple d’activation specifique en phase homogene. Tetrahedron Letters. 32 (21): 2363-2366. doi: 10.1016/ S0040-4039(00)79924-2
  61. Krstić LJ, Sukdolak S, Sukdolak S(2002) An efficient synthesis of warfarin acetals on montmorillonite clay k-10 with microwaves. Journal of the Serbian Chemical Society. 67 (5): 325-329. doi: 10.2298/JSC0205325K
  62. Chitrala T, Garg A, Rohith GK, Roshini H, Jena S, Khan FRN (2021) Diversity oriented synthesis of oxygen-heterocycles, warfarin analogs utilizing microwave-assisted dimethyl urea-based deep eutectic solvents. Polycyclic Aromatic Compounds. 42 (2): 1-11. doi: 10.1080/10406638.2021.1912123
  63. Dong Z, Feng J, Cao W, Liu X, Lin L, Feng X (2011) N, N′-dioxide-Nickel (II) complex catalyzed asymmetric Michael addition of cyclic 1, 3-dicarbonyl compounds to β, γ-unsaturated α-ketoesters. Tetrahedron Letters. 52 (27): 3433-3436. doi: 10.1016/j.tetlet.2011.04.089
  64. Rogozińska M, Adamkiewicz A, Mlynarski J (2011) Efficient ‘on water’ organocatalytic protocol for the synthesis of optically pure warfarin anticoagulant. Green Chemistry. 13 (5): 1155-1157. doi: 10.1039/C1GC1 5118E
  65. Rogozińska-Szymczak M, Mlynarski J (2014) Asymmetric synthesis of warfarin and its analogues on water. Tetrahedron: Asymmetry. 25 (10-11): 813-820. doi: 10.1016/j.tetasy.2014.04.008
  66. Yang H-M, Li L, Jiang K-Z, Jiang J-X, Lai G-Q, Xu L-W (2010) Highly enantioselective synthesis of warfarin and its analogs by means of cooperative LiClO4/DPEN-catalyzed Michael reaction: enantioselectivity enhancement and mechanism. Tetrahedron. 66 (51): 9708-9713. doi: 10.1016/j.tet.2021.10.032
  67. Ju Y-D, Xu L-W, Li L, Lai G-Q, Qui H-Y, Jiang J-X, Lu Y (2008) Noyori’s Ts-DPEN ligand: An efficient bifunctional primary amine-based organocatalyst in enantio-and diastereoselective Michael addition of 1, 3-dicarbonyl indane compounds to nitroolefins. Tetrahedron Letters. 49 (48): 6773-6777. doi: 10.1016/j.tetlet. 2008.09.025
  68. Shi T, Guo Z, Yu H, Xie J, Zhong Y, Zhu W (2013) Atom‐economic synthesis of optically active warfarin anticoagulant over a chiral MOF organocatalyst. Advanced Synthesis and Catalysis. 355 (13): 2538-2543. doi: 10.1002/adsc.201300554
  69. Gutmann B, Cantillo D, Kappe CO (2015) Continuous‐flow technology-a tool for the safe manufacturing of active pharmaceutical ingredients. Angewandte Chemie International Edition. 54 (23): 6688-6728. doi: 10.1002 /anie.201409318
  70. Newman SG, Jensen KF (2013) The role of flow in green chemistry and engineering. Green Chemistry. 15 (6): 1456-1472. doi: 10.1039/C3GC40374B
  71. Wegner J, Ceylan S, Kirschning A (2012) Flow chemistry-a key enabling technology for (Multistep) organic synthesis. Advanced Synthesis and Catalysis. 354 (1): 17-57. doi: 10.1002/adsc.201100584
  72. Barrulas P, Benaglia M, Burke AJ (2014) Synthesis of novel cinchona-amino acid hybrid organocatalysts for asymmetric catalysis. Tetrahedron: Asymmetry. 25 (12): 923-935. doi: 10.1016/j.tetasy. 2014.05.003
  73. Porta R, Benglia M, Coccia F, Rossi S, Puglisi A (2015) Enantioselective organocatalysis in microreactors: Continuous flow synthesis of a (S)-pregabalin precursor and (S)-warfarin. Symmetry. 7 (3): 1395-1409. doi: 10.3390/sym7031395
  74. Martins MAP, Frizzo CP, Moreira DN, Rosa FA, Marzari MRB, Zanatta N, Bonacorso HG (2008) Synthesis of β-enaminones by ionic liquid catalysis: A one-pot condensation under solvent-free conditions. Catalysis Communications. 9 (6): 1375-1378. doi: 10.1016/j.catcom.2007.11.037
  75. Tanaka K, Toda F (2000) Solvent-free organic synthesis. Chemical Reviews. 100 (3): 1025-1074. doi: 10.1021/ cr940089p
  76. Monfared A, Esmaeeli Z (2016) A one-pot condensation for synthesis 2-methyl-4-phenylpyrano[3, 2-c] chromen-5(4H)-one and synthesis of warfarin by ionic liquid catalysis. Iranian Journal of Pharmaceutical Research. 15 (3): 343-367. doi: 10.22037/IJPR.2016.1885
  77. Cai J-F, Guan Z, He Y-H (2011) The lipase-catalyzed asymmetric C-C Michael addition. Journal of Molecular Catalysis B: Enzymatic. 68 (3-4): 240-244. doi: 10.1016/j.molcatb.2010.11.011
  78. Xie BH, Guan Z, He YH (2012) Promiscuous enzyme‐catalyzed Michael addition: synthesis of warfarin and derivatives. Journal of Chemical Technology and Biotechnology. 87 (12): 1709-1714. doi: 10.1002/jctb.3830

Submitted date:
11/12/2024

Reviewed date:
11/28/2024

Accepted date:
12/05/2024

Publication date:
12/07/2024

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