Synthesis and characterization of new 8-aryl-1,3-dimethylxanthine derivatives
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Dosyalar
Tarih
2023
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Yayıncı
Bursa Teknik Üniversitesi, Lisansüstü Eğitim Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Ksantin, pürin adı verilen heterosiklik aromatik organik bir bileşiktir. Kahve yaprakları ve çekirdeklerinde bulunan kafein, siyah ve yeşil çay yapraklarındaki teofilin ve teobroma, kakao ağacının tohumlarındaki teobromin gibi doğada pek çok türevi bulunmaktadır. İki önemli pürin türevi olan adenin ve guanin iskeletlerinin ksantin iskeleti ile benzerliği, ksantinin önemli bir terapötik molekül olduğunu göstermektedir. Bu nedenle son zamanlarda çeşitli hastalıkların tedavisi için ksantin türevlerinin kullanımı hedeflenmektedir. Ksantin moleküllerindeki sübstitüe grupların çeşitliliği, anti-Alzheimer ve anti-parkinsonizm, anti-kanser, anti-astım ve bronkodilatasyon, anti-depresan, anti-inflamatuar, anti-diyabetik, diüretik, anti-mikrobiyal, sirtuin inhibitörleri ve adenosin reseptör alt tiplerinin ligandları dahil olmak üzere birçok tedavide ilaç adayı olmasına önem verilmektedir. Moleküldeki C-8 pozisyonu, biyolojik aktivite üzerinde önemli bir etkiye sahiptir. Bu tez çalışmasında, salisilaldehit, 5,6-diamino-1,3-dimetilurasil ile reaksiyona sokularak Schiff-bazları oluşturulmuştur. Elde edilen Schiff bazlarının, iyot kullanılarak gerçekleştirilen halka kapama reaksiyonu sonucu yeni 8-sübstitüe ksantin türevleri sentezlenmiştir. Spektroskopik yöntemler kullanılarak sentezlenen 8-aril ksantin türevlerinin yapı tayini gerçekleştirilmiştir. Ksantin türevlerinin su ve organik çözücülerdeki sınırlı çözünürlüğü bu bileşiklerin tam karakterizasyonunun gerçekleştirilmesinde, özellikle 13CNMR spektrumlarının eldesinde sorun teşkil etmiştir. 8-Aril ksantinlerin çözünürlüğünü arttırmak amacıyla deneysel çalışmalarda bulunulmuştur. Bu amaçla ksantin türevinin sodyum hidroksit ile reaksiyonu sonucu ksantin sodyum tuzlarının elde edilmesi planlanmıştır. Ksantin sodyum tuzlarının suda çözünür oldukları belirlenmiş ancak D2O ile gerçekleştirilen NMR analizlerinden beklenen sonuç elde edilememiştir. Son olarak salisilaldehitin aromatik hidroksili üzerinden gerçekleştirilecek sililleme reaksiyonu ile ksantin türevlerinin organik çözücülerdeki çözünürlüğünün arttırılması hedeflenmiştir. Silillenmiş aldehitin, 5,6-diamino-1,3-dimetilurasil ile reaksiyonu sonucu silillenmiş Schiff-bazları elde edilmiştir. Son adım da ise halka kapama reaksiyonu ile diklorometan içinde çözünür silillenmiş ksantin ürünü elde edilmiştir.
Xanthine is a heterocyclic aromatic organic compound belongs to purine bases. It has many derivatives present in nature, such as caffeine in coffee leaves and beans, theophylline in black and green tea leaves, and theobromine in seeds of the Theobroma cocoa tree. Because of the similarity between the xanthine skeleton and the skeleton of two important purine derivatives, adenine and guanine, it is considered as an important therapeutic molecule. Thus, recently the treatments of various diseases are targeted by xanthine derivatives. The diversity of the substituted groups in xanthine molecules gives it importance to be a drug candidate in many treatments, including anti-parkinsonism and anti-Alzheimer's, anti-cancer, anti-asthmatic and bronchodilation, anti-diabetic, anti-depressant, anti-inflammatory, diuretic, anti-microbial, sirtuin inhibitors and ligands of adenosine receptor subtypes. C-8 position in the xanthine molecule have a significant impact on biological activity. So many prodrugs were designed through 8-substitution. In this thesis, new 8-substituted xanthine derivatives were synthesized by reacting the corresponding aldehydes with 5,6-diamino-1,3-dimethyluracil to form Schiff bases and then performing the ring-closing reaction using iodine. Spectroscopic methods were applied to confirm the structures of the synthesized xanthine derivatives. The poor solubility of these derivatives in water and common organic solvents limited the techniques used to characterize the products, especially the 13CNMR analysis. Experimental attempts have been made to solve this solubility problem. Thus, the xanthine derivatives were reacted with sodium hydroxide to form xanthine sodium salts. The solubility of the products in water significantly improved and the product completely dissolved in water, but the expected results could not be obtained from NMR analysis which was performed in D2O. Then we planned to improve the solubility of the products in common organic solvents by converting it to silyl derivatives. The silyl derived Schiff bases were obtained by reacting silylated salicylaldehyde derivative and 5,6-diamino-1,3-dimethyluracil. In the final step, silyl derived xanthine derivative, which was completely soluble in dichloromethane, was obtained.
Xanthine is a heterocyclic aromatic organic compound belongs to purine bases. It has many derivatives present in nature, such as caffeine in coffee leaves and beans, theophylline in black and green tea leaves, and theobromine in seeds of the Theobroma cocoa tree. Because of the similarity between the xanthine skeleton and the skeleton of two important purine derivatives, adenine and guanine, it is considered as an important therapeutic molecule. Thus, recently the treatments of various diseases are targeted by xanthine derivatives. The diversity of the substituted groups in xanthine molecules gives it importance to be a drug candidate in many treatments, including anti-parkinsonism and anti-Alzheimer's, anti-cancer, anti-asthmatic and bronchodilation, anti-diabetic, anti-depressant, anti-inflammatory, diuretic, anti-microbial, sirtuin inhibitors and ligands of adenosine receptor subtypes. C-8 position in the xanthine molecule have a significant impact on biological activity. So many prodrugs were designed through 8-substitution. In this thesis, new 8-substituted xanthine derivatives were synthesized by reacting the corresponding aldehydes with 5,6-diamino-1,3-dimethyluracil to form Schiff bases and then performing the ring-closing reaction using iodine. Spectroscopic methods were applied to confirm the structures of the synthesized xanthine derivatives. The poor solubility of these derivatives in water and common organic solvents limited the techniques used to characterize the products, especially the 13CNMR analysis. Experimental attempts have been made to solve this solubility problem. Thus, the xanthine derivatives were reacted with sodium hydroxide to form xanthine sodium salts. The solubility of the products in water significantly improved and the product completely dissolved in water, but the expected results could not be obtained from NMR analysis which was performed in D2O. Then we planned to improve the solubility of the products in common organic solvents by converting it to silyl derivatives. The silyl derived Schiff bases were obtained by reacting silylated salicylaldehyde derivative and 5,6-diamino-1,3-dimethyluracil. In the final step, silyl derived xanthine derivative, which was completely soluble in dichloromethane, was obtained.
Açıklama
Anahtar Kelimeler
Kimya, Chemistry
