Publication: Karvakrolden hareketle tiyoeter grubu içeren bazı yeni heterohalkalı bileşiklerin sentezi ve biyolojik etkileri
Abstract
1.ÖZET Karvakrolden hareketle tiyoeter grubu içeren bazı yeni heterohalkalı bileşiklerin sentezi ve biyolojik etkileri Öğrenci Adı: İlker DEMİRBOLAT Danışman Adı: Prof. Dr. İlkay KÜÇÜKGÜZEL Amaç: Nonstreoidal antiinflamatuvar ilaçların uzun vadeli kullanımlarının çeşitli yan etkiler geliştiğinden tedavi için alternatif makromoleküler hedefler aranmaktadır. mPGES-1 enzimi bu hedeflerden birisi olup gerek inflamasyon mekanizması, gerek COX-2 enzimine olan yapısal benzerlikleri, gerekse kanser ve romatoid artirit gibi inflamasyonun önem kazandığı hastalıklarla olan bağlantısı sebebiyle ilgiyi üzerine çekmektedir. Bu sebeple mPGES-1 inhibisyonunu hedef alacak bir dizi molekülün geliştirilmesi amaçlanmıştır. Gereç ve yöntem: mPGES-1 enzimine karşı literatür taraması ve bilgisayar ortamında moleküler modelleme çalışmaları yapılarak enzime bağlanma dereceleri yüksek moleküler iskeletler belirlenmiştir, ilgili bileşikler sentezlenmiş spektral veriler ile yapıları aydınlatılmış ve aktivite çalışmaları yapılmıştır. Bulgular: Sentezlenen moleküllerin yapısı IR, 1H-NMR, 13C-NMR, kütle spektrumu gibi spektral yöntemler ile belirlenmiş, saflık dereceleri HPLC ile kontrol edilmiştir. Bileşiklerin antikanser etki çalışmaları, kaspaz enzim aktiviteler, mitokondriyal membran potansiyelleri, mPGES-1 inhibisyon etki çalışmaları, COX-1 ve COX-2 enzim inhibisyon çalışmaları ve yara iyileşme üzerine etkileri tespit edilmiştir. Sonuç: Bu çalışma kapsamında seri halde sentezlenen bileşiklerin içerinden en aktifinin 26 numaralı bileşik olduğu tespit edildi. MTT testi ile IC50 değerinin 12.8 µM olarak bulunan bileşiğin, mitokondriyal yol olarak da adlandırılan kaspaz-9 sinyal mekanizmasını indükleyerek doza bağlı bir şekilde apoptozu indüklediği, buna Ek olarak bileşik 26, apoptozun içsel yolunun bir kanıtı olarak MCF-7 hücrelerinde MMP'yi önemli ölçüde azalttığı tespit edilmiştir. azol, mPGES-1 inhibisyonu, tiyoeter, karvakrol
2.SUMMARY Synthesis and biological effects of some novel heterocyclic compounds containing thioether group derived from carvacrol Student Name: İlker DEMİRBOLAT Name of Supervisor: Prof. Dr. İlkay KÜÇÜKGÜZEL Objective: NSAID perform their actions over COX enzyme inhibition. Medical treatment needs alternative macromolecular targets due to the side effects of long-term usage of NSAID, The mPGES-1 is one these targets which has an important role in inflammation and also has structural similarities with COX-2. It is also related with cancer and rheumatoid arthritis in which inflammation have important roles. Therefore, we aimed to develop some novel mPGES-1 inhibitor molecules. Material and methods: Possible active molecular skeletons against mPGES-1 were determined via literature search and computer assisted molecular docking studies. Different substituents were added to selected skeletons and structures of synthesised molecules were determined with spectral technics. Results: Chemical structures of synthesised molecules were determined with spectral studies such as IR, 1H-NMR, 13C-NMR, mass spectrums. Purity of the compounds were evaluated with HPLC. Anticancer activity studies, caspase enzyme activities, mitochondrial membrane potentials, mPGES-1 inhibition effects, COX-1 and COX-2 enzyme inhibition and wound healing activities of the synthesized compounds were determined. Conclusion: The IC50 value of the most active compound 26 was determined as 12.8 µM using a cell viability assay (MTT assay) and xCELLigence real-time cell analysis. This compound induced apoptosis in a dose-dependent manner, by inducing caspase-9 signalling mechanism, also called the mitochondrial pathway. In addition, compound 26 significantly decreased the MMP in MCF-7 cells as evidence for intrinsic pathway of apoptosis. azole, mPGES-1 inhibition, thioether, carvacrol
2.SUMMARY Synthesis and biological effects of some novel heterocyclic compounds containing thioether group derived from carvacrol Student Name: İlker DEMİRBOLAT Name of Supervisor: Prof. Dr. İlkay KÜÇÜKGÜZEL Objective: NSAID perform their actions over COX enzyme inhibition. Medical treatment needs alternative macromolecular targets due to the side effects of long-term usage of NSAID, The mPGES-1 is one these targets which has an important role in inflammation and also has structural similarities with COX-2. It is also related with cancer and rheumatoid arthritis in which inflammation have important roles. Therefore, we aimed to develop some novel mPGES-1 inhibitor molecules. Material and methods: Possible active molecular skeletons against mPGES-1 were determined via literature search and computer assisted molecular docking studies. Different substituents were added to selected skeletons and structures of synthesised molecules were determined with spectral technics. Results: Chemical structures of synthesised molecules were determined with spectral studies such as IR, 1H-NMR, 13C-NMR, mass spectrums. Purity of the compounds were evaluated with HPLC. Anticancer activity studies, caspase enzyme activities, mitochondrial membrane potentials, mPGES-1 inhibition effects, COX-1 and COX-2 enzyme inhibition and wound healing activities of the synthesized compounds were determined. Conclusion: The IC50 value of the most active compound 26 was determined as 12.8 µM using a cell viability assay (MTT assay) and xCELLigence real-time cell analysis. This compound induced apoptosis in a dose-dependent manner, by inducing caspase-9 signalling mechanism, also called the mitochondrial pathway. In addition, compound 26 significantly decreased the MMP in MCF-7 cells as evidence for intrinsic pathway of apoptosis. azole, mPGES-1 inhibition, thioether, carvacrol