Fluoksetin ve Norfluoksetinin Sentezi Üzerine Çalışmalar ve Antioksidant Özelliğinin Araştırılması

Öz

İki halkalı antideprasan ilaç olan norfluoksetin ve fluoksetinin sentezi için, başlangıç materyali olarak kolayca bulunabilen sirenlerin epoksidasyonunun kullanılmasını içeren yeni, pratik ve kısa bir yöntem geliştirilmiştir. Bu çalışma, norfluoksetin ve fluoksetinin kısa bir yolla yeni yöntemlerin yapımında, ticari olarak ilgi gören bu bileşiklerin sentezinde uygulama alanı bulmuştur. Ayrıca, başlıkta verilen bu iki bileşiğin antioksidan aktivitesi CUPRAC (bakır indirgeyici antioksidan kapasite yöntemi) yöntemi ve fluoksetin ve norfluoeksetinin TEAC (Trolox-Eşdeğer Antioksidan Kapasite) katsayısı ile değerlendirilmiştir. Bu çalışmada antioksidan özelliğinin araştırılması literatürde ilk defa yapılmıştır. Aynı zamanda, Bu metot ile yüzde verim, reaksiyon şartları ve reaksiyon basamağının kısalığı ile de avantajlar sağlamaktadır. Sentezlenen bileşiklerin karekterizasyonu 1H- NMR, 13C-NMR IR ve MS-kütle spektroskopisi ile yapılmıştır.

Anahtar Kelimeler

• Prozac
• Antidepresan
• Antioksidanlar
• Fluoksetin
• Epoksidasyon

Studies on The Synthesis of Fluoxetine and Norfluoxetine and Investigation of their Antioxidant Properties

Öz

A new, practical and short method has been developed for the synthesis of bicyclic antidepressant drugs norfluoxetine and fluoxetine, which involves the use of epoxidation of easily available sirens as starting materials. This study has found application in the synthesis of these compounds of commercial interest, in the construction of new methods of norfluoxetine and fluoxetine in a short way. Additionally, the antioxidant activity of these two compounds given in the title was evaluated by the CUPRAC (copper-reducing antioxidant capacity method) method and the TEAC (Trolox-Equivalent Antioxidant Capacity) coefficient of fluoxetine and norfluoexetin. In this study, the antioxidant properties were investigated for the first time in the literature. At the same time, this method provides advantages in terms of percentage yield, reaction conditions and shortness of the reaction step. Characterization of the synthesized compounds was made by 1H-NMR, 13C-NMR IR and MS-mass spectroscopy.

Anahtar Kelimeler

• Prozac
• Antidepressant
• Antioxidants
• Fluoxetine
• Epoxidation

Kaynakça

1. Bianchi M, Rossoni G, Sacerdote P, Panerai AE, Berti F. 1995. Effects of chlomipramine and fluoxetine on subcutaneous carrageenin-induced inflammation in the rat. Inflamm Res, 44: 466-469.
2. Bianchi M, Sacerdote P, Panerai AE. 1994. Fluoxetine reduces inflammatory edema in the rat: involvement of the pituitary-adrenal axis. Eur j Pharmacol, 263: 81-84.
3. Bracher F, Litz T. 1996. An efficient chemoenzymatic route to the antidepressants (R)-fluoxetine and (R)-tomoxetine. Bioorg Med Chem, 4: 877-880.
4. Caiaffo V, Oliveira BDR, Se SA FB, Evencio Neto J. 2016. Anti-inflammatory, antiapoptotic, and antioxidant activity of fluoxetine. Pharmacol Res Perspect, 4: e00231.
5. Chini M, Crotti P, Favero L, Macchia F. 1991. Easy direct stereo-and regioselective formation of β-hydroxy nitriles by reaction of 1, 2-epoxides with potassium cyanide in the presence of metal salts. Tetrahedron Lett, 32: 4775-4778.
6. Djordjevic J, Djordjevic A, Adzic M, Elaković I, Matić G, Radojcic MB. 2011. Fluoxetine affects antioxidant system and promotes apoptotic signaling in Wistar rat liver. Eur J Pharmacol, 659: 61-66.
7. Gao Y, Sharpless KB. 1988. Asymmetric Synthesis of both enantiomers of tomoxetine and fluoxetine. Selective reduction of 2,3-epoxycinnamyl alcohol with Red-Al. J Org Chem, 53: 4081-4084.
8. Grutters MM, Müller C, Vogt D. 2006. Highly selective cobalt-catalyzed hydrovinylation of styrene. J Am Chem Soc, 128: 7414-7415.

9. Hilborn JW, Lu ZH, Jurgens AR, Fang Q K, Byers P, Wald SA, Senanayake CH. 2001. A practical asymmetric synthesis of (R)-fluoxetine and its major metabolite (R)-norfluoxetine. Tetrahedron Lett, 42: 8919-8921.
10. Juarez-Luna PJ, Mendoza S, Cardenas A. 2019. Comparison of electrochemical methods using CUPRAC, DPPH, and carbon paste electrodes for the quantification of antioxidants in food oils. Analytical Methods, 11: 5755-5760.
11. Kakei HT, Ohshima N, Shibasaki TM. 2005. Efficient synthesis of chiral α- and β-hydroxy amides: Application to the synthesis of (R)-fluoxetine. Angew Chem Int Ed, 43: 317-320.
12. Koenig TM, Mitchell D. 1994. A convenient method for preparing enantiomerically pure norfluoxetine, fluoxetine and tomoxetine. Tetrahedron Lett, 35: 1339-1342.
13. Kohen R, Nyska A. 2002. Invited review: oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol, 30: 620-650.
14. Kolla N, Wei Z, Richardson JS, Li XM. 2005. Amitriptyline and fluoxetine protect PC12 cells from cell death induced by hydrogen peroxide. J. Psychiatry Neurosci, 30: 196-201.
15. Korey EJ, Reichhard GA. 1989. Enantioselective and practical syntheses of R- and S-fluoxetines. Tetrahedron Lett, 30: 5207-5210.
16. Kumar A, Ner DH, Dike SY. 1991. A new chemoenzymatic enantioselective synthesis of R-(−)-tomoxetine, (R)- and (S)-fluoxetine. Tetrahedron Lett, 32: 1901-1904.
17. Kumar P, Upadhyay RK, Pandey RK. 2004. Asymmetric dihydroxylation route to (R)-isoprenaline,(R)-norfluoxetine and (R)-fluoxetine. Tetrahedron Asymmetry, 15: 3955-3959.
18. Lapis AAM, De Fatima A, Martis JED, Costa VEU, Pilli RA. 2005. Asymmetric reduction of prochiral ketones using in situ generated oxazaborolidine derived from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol. An efficient synthesis of enantiopure (R)-tomoxetine. 2005. Tetrahedron Lett, 46: 495-498.
19. Li Y, Li Z, Li F, Wang Q, Tao F. 2005. Preparation of polymer-supported Ru-TsDPEN catalysts and use for enantioselective synthesis of (S)-fluoxetine. Org Biomol Chem, 3: 2513-2518.
20. Piparaki S, Parissi-Poulou M.1993. Use of Cyclodextrins as chiral selectors for direct resolution of the enantiomers of fluoxetine and its metabolite norfluoxetine by HPLC Chirality, 5: 258-266.
21. Robertson DW, Jones ND, Swartzendruber JK, Wong DT. 1988b. Molecular structure of fluoxetine hydrochloride, a highly selective serotonin-uptake inhibitor. J Med Chem, 31: 185-189.
22. Robertson DW, Krushinski JH, Fuller RW, Leander JD. 1988a. Absolute configurations and pharmacological activities of the optical isomers of fluoxetine, a selective serotonin-uptake inhibitor. J Med Chem, 31: 1412-1417.
23. Rossi A, Barraco A, Donda P. 2004. Fluoxetine: a review on evidence based medicine. Ann Gen Hosp Psychiatry, 3: 1-8.
24. Serdaroğlu G, Uludag N, Sagumar P, Rajkumar P. 2021. (-)-Tubifolidine as strychnos indole alkaloid: Spectroscopic charactarization (FT-IR, NMR, UV-Vis), antioxidant activity, molecular docking, and DFT studies. J Mol Struct, 1244: 130978.
25. Stark P, Hardison CD. 1985. A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in outpatients with major depressive disorder. J Clin Psychiatry, 46: 53-58.
26. Uludag N, Serdaroğlu G. 2021. An efficient studies on C-2 cyanomethylation of the indole synthesis: The electronic and spectroscopic characterization (FT-IR, NMR, UV-Vis), antioxidant activity, and theoretical calculationsJ Mol Struct, 1247: 131416.
27. Uludag N. 2023. Çinko-triflat katalizörü kullanılarak farklı sübstitüye izokumarin türevlerinin sentezi. BSJ Eng Sci, 6: 127-131.
28. Wang Y, Wu Z, Li Z, Zhou XG. 2009. Asymmetric epoxidation of styrenes catalyzed by molybdenum complexes with amino alcohol ligands. Tetrahedron Lett, 50: 2509-2511.
29. Wei Y, Xuan Q, Zhou Y, Song Q. 2018. Reductive N-alkylation of primary and secondary amines using carboxylic acids and borazane under mild conditions. Org. Chem. Front, 5: 3510-3514.
30. Wirth DD, Baertschi SW, Johnson RA, Maple SR, Miller MS, Hallenback DK, Gregg SM. 1995. Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine. J Pharm Sci, 87: 31-39.
31. Wong DT, Bymaster FP, Englman EA. 1995. Prozac (fluoxetine, lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: Twenty years since its first publication. Life Sci, 57: 411-441.
32. Zafir A, Banu N. 2007. Antioxidant potential of fluoxetine in comparison to curcuma longa in restraint-stressed rats. Eur J Pharmacol, 572: 23-31.
33. Zerbe RL, Rowe H, Enas GG, Wong D, Farid N, Lemberger L. 1985. Clinical pharmacology of tomoxetine, a potential antidepressant. J Pharmacol Exp Ther, 232: 139-143.