Publication: Flurbiprofen türevi bileşiklerin sentezi ve antikanser etkilerinin araştırılması
Abstract
Amaç: Non-steroidal bir etken madde olan ve literatürde antikanser aktiviteye de sahip olduğu bildirilen flurbiprofen bileşiğinden hareketle, meme kanseri üzerinde antikanser aktivite göstermesi beklenen yeni 1,2,4-triazol ve tiyoeter bileşiklerinin tasarımı, sentezlenmesi ve in-vitro aktivite çalışmalarının yapılması amaçlanmıştır. Gereç ve Yöntem: Flurbiprofen bileşiğinden hareketle, derişik sülfirik asit katalizörlüğünde metanol ile reaksiyonu sonucu (±)(R,S)-metil 2-[(3-fluoro-4-fenil)fenil]propanoat (1), metil esterinin hidrazin hidrat ile reaksiyonuyla ise (±)(R,S)-2-[(3-fluoro-4-fenil)fenil]propan hidrazit bileşiği (2) elde edilmiştir. Sentezlenen hidrazit bileşiğinin metil izotiyosiyanat ile reaksiyonuyla (±)(R,S)-1-[2-[(3-fluoro-4-fenil)fenil]propanoil]-4-metiltiyosemikarbazit (3) bileşiği ve bu bileşiğin 4N NaOH ile ısıtılması yoluyla siklizasyon sonucu (±)(R,S)-5-[1-[(3-fluoro-4-fenil)fenil]etil]-4-metil-4H-1,2,4-triazol-3-tiyon (4) bileşiği sentezlenmiştir. Bu bileşiğin çeşitli benzil klorür türevleri ile bazik ortamda reaksiyona girmesiyle ise tiyoeter bileşikleri (±)(R,S)-4-metil-5-[1-[(3-fluoro-4-fenil)fenil]etil]-3-[(sübstitüebenzil)tiyo]-4H-1,2,4-triazol (5a-r) sentezlenmiştir. Bulgular: Flurbiprofen üzerinden sentezlenen 1,2,4-triazol ve tiyoeter bileşikleri orijinal olup saflık kontrolleri ince tabaka kromatografisi ve elementel analiz; yapı karakterizasyonları ise FT-IR, 1H NMR, 13C NMR ile 19F NMR (5l) spektral analiz metotları aracılığıyla kanıtlanmıştır. Yapıları aydınlatılan bileşiklerin in-vitro antikanser aktivite çalışmaları, meme kanseri hücre hattı (MDA-MB231) üzerinde WST-1 kolorimetrik metodu kullanılarak yapılmıştır. Ayrıca bileşiklerin metiyonin aminopeptidaz 2 enzimine karşı bağlanma enerjileri (ΔG Kcal/ mol) ve inhibisyon sabiti (Ki) hesaplanmıştır. Sonuç: Meme kanseri hücre hattı (MDA-MB231) üzerinde bileşik 3 ve bileşik 5a 20 μg/ ml’de, bileşik 5b ise 15 μg/ ml ve 20 μg/ ml’de sitotoksik etki göstermiştir. Bileşik 5l’nin 20 μg/ ml konsantrasyonda sitositatik etkili olduğu bulunmuştur. Bileşik 5l-doksorubisin kombinasyonu çalışılmış, hücre canlılığı %7 olarak tespit edilmiştir ve bu durum kemoterapötik ilaç adayı olabileceğini göstermiştir.
Objective: Based on the flurbiprofen, which is a non-steroidal anti-inflammatory drug and has anticancer activity in the literature, it is aimed to design, synthesize, and conduct in vitro activity studies of novel 1,2,4-triazole and thioether compounds that are expected to show anticancer activity in breast cancer. Materials and Methods: (±)(R,S)-Methyl 2-[2-fluoro-(1,1'-biphenyl)-4-yl]propanoate (1) was obtained as a result of the reaction of flurbiprofen with methanol in the presence of concentrated sulfuric acid, and the reaction of methyl ester (1) with hydrazine hydrate (±)(R,S)-2-[2-fluoro-(1,1'-biphenyl)-4-yl]propanehydrazide (2) was synthesized. (±)(R,S)-2-{2-[2-fluoro-(1,1'-biphenyl)-4-yl)]propanoyl}-N-methylhydrazinecarbothioamide (3) was obtained by the reaction of compound 2 with methyl isothiocyanate, and (±)(R,S)-3-{1-[2-fluoro-(1,1'-biphenyl)-4-yl]ethyl}-4-methyl-1H-1,2,4-triazole-5(4H)-thione (4) was synthesized by the cyclization of the thiosemicarbazide compound (3) in 4N NaOH. (±)(R,S)-3-(Substitutedbenzylthio)-4-methyl-5-{1-[2-fluoro-(1,1'-biphenyl)-4-yl]ethyl}-4H-1,2,4-triazoles (5a-r) were synthesized with compound 4 and various benzyl chloride derivatives in a basic medium. Results: The 1,2,4-triazole and thioether compounds synthesized from flurbiprofen are original and their purity was checked by thin layer chromatography and elemental analysis; the structure characterizations were proved using FT-IR, 1H NMR, 13C NMR, and 19F NMR (5l) spectroscopic analysis methods. In-vitro anticancer activity studies of the compounds whose structures were elucidated were performed using the WST-1 colorimetric method on the breast cancer cell line (MDA-MB231). In addition, the binding energies (ΔG Kcal/ mol) and inhibition constant (Ki) of the compounds against the methionine aminopeptidase 2 enzyme were calculated. Conclusion: On the MDA-MB231 cells, compounds 3 and 5a showed cytotoxic effects at 20 μg/ ml, and compound 5b at 15 μg/ ml and 20 μg/ ml. Compound 5l was found to be cytostatic at a concentration of 20 μg/ ml. As a result of the combination of compound 5l-doxorubicin, cell viability was determined as 7%, indicating that it can be a chemotherapeutic drug candidate.
Objective: Based on the flurbiprofen, which is a non-steroidal anti-inflammatory drug and has anticancer activity in the literature, it is aimed to design, synthesize, and conduct in vitro activity studies of novel 1,2,4-triazole and thioether compounds that are expected to show anticancer activity in breast cancer. Materials and Methods: (±)(R,S)-Methyl 2-[2-fluoro-(1,1'-biphenyl)-4-yl]propanoate (1) was obtained as a result of the reaction of flurbiprofen with methanol in the presence of concentrated sulfuric acid, and the reaction of methyl ester (1) with hydrazine hydrate (±)(R,S)-2-[2-fluoro-(1,1'-biphenyl)-4-yl]propanehydrazide (2) was synthesized. (±)(R,S)-2-{2-[2-fluoro-(1,1'-biphenyl)-4-yl)]propanoyl}-N-methylhydrazinecarbothioamide (3) was obtained by the reaction of compound 2 with methyl isothiocyanate, and (±)(R,S)-3-{1-[2-fluoro-(1,1'-biphenyl)-4-yl]ethyl}-4-methyl-1H-1,2,4-triazole-5(4H)-thione (4) was synthesized by the cyclization of the thiosemicarbazide compound (3) in 4N NaOH. (±)(R,S)-3-(Substitutedbenzylthio)-4-methyl-5-{1-[2-fluoro-(1,1'-biphenyl)-4-yl]ethyl}-4H-1,2,4-triazoles (5a-r) were synthesized with compound 4 and various benzyl chloride derivatives in a basic medium. Results: The 1,2,4-triazole and thioether compounds synthesized from flurbiprofen are original and their purity was checked by thin layer chromatography and elemental analysis; the structure characterizations were proved using FT-IR, 1H NMR, 13C NMR, and 19F NMR (5l) spectroscopic analysis methods. In-vitro anticancer activity studies of the compounds whose structures were elucidated were performed using the WST-1 colorimetric method on the breast cancer cell line (MDA-MB231). In addition, the binding energies (ΔG Kcal/ mol) and inhibition constant (Ki) of the compounds against the methionine aminopeptidase 2 enzyme were calculated. Conclusion: On the MDA-MB231 cells, compounds 3 and 5a showed cytotoxic effects at 20 μg/ ml, and compound 5b at 15 μg/ ml and 20 μg/ ml. Compound 5l was found to be cytostatic at a concentration of 20 μg/ ml. As a result of the combination of compound 5l-doxorubicin, cell viability was determined as 7%, indicating that it can be a chemotherapeutic drug candidate.