Yeni ariliden urasil türevlerinin sentezi, yapı tayini ve sitotoksik aktivite çalışmaları
Küçük Resim Yok
Tarih
2021
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Bursa Teknik Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Günümüzde DNA, replikasyon ve transkripsiyon mekanizmalarındaki kritik rolü nedeniyle, antibiyotik, antikanser ve antiviral ilaçların geliştirilmesinde ana hedeflerden biri durumundadır. Kanser, aids, sıtma ve birçok bakteriyel hastalıkta DNA'ya bağlanan ilaçların etkileri bilinmektedir. Bu nedenle biyoorganik kimya alanında yapılan güncel çalışmalar, cisplatin gibi bilinen komplekslerden daha etkili olan ve daha düşük doku direnci ile potansiyel antikanser ilaç öncüsü olabilecek yeni DNA hedefli bileşiklerin sentezini içermektedir. Schiff bazları, yüksek katalitik ve biyolojik aktiviteleri nedeniyle uzun yıllardır çalışılmaktadır. Pratik sentez ve izolasyon yöntemleri, geçiş metallerine karşı ilgileri nedeniyle çok çeşitli uygulama alanları mevcuttur. Urasil türevleri, önemli bir pirimidin sınıfı olarak kabul edilir. Antitümör, antialerjik ve antibakteriyel gibi farklı farmakolojik aktivitelere sahip türevleri literatürde yer almaktadır. 5-Florourasil antikanser ilaç olarak kullanılmaktadır. Aminourasil türevleri, biyolojik açıdan önemli birçok urasil bileşiğinin sentezi için başlangıç maddesi olarak kullanılmaktadır. 5-Aminourasil, güçlü hidrojen bağı oluşturabilme kabiliyeti, laktim-laktam tautomerleri üzerinden sunduğu çok fonksiyonlu yapısı ve türevlendirmeye uygun fonksiyonel grupları nedeniyle DNA bağlanma çalışmaları açısından da dikkat çekici bir moleküldür. Bu tez çalışmasının hedef molekülleri, 5-aminourasil türevi Schiff bazlarının in silico DNA bağlanma çalışmalarından elde edilen sonuçlar doğrultusunda şekillendirildi. İlk aşamada molekül modelleme çalışmaları ile DNA bağlanma potansiyeli yüksek olan bileşikler belirlendi. Başlangıç maddesi olarak 5-aminourasil, 5,6-diamino-1,3-dimetilurasil ve farklı fonksiyonel gruplara sahip salisilaldehit biles?ikleri kullanıldı. Reaksiyonlar sonunda, yeni, 8 adet 5-aminourasil türevi Schiff bazı ve 19 adet 5,6-diamino-1,3-dimetilurasil Schiff bazı sentezlendi. Ürünler reaksiyon ortamından süzülerek ayrıldı ve saf olarak elde edildi. Elde edilen bu biles?iklerin yapıları FT-IR, 1H-NMR, 13C-NMR ve elementel analiz yöntemleri ile aydınlatıldı. MTT [3-(4,5-dimetil-2-tiazoil)-2,5-difenil-2H-tetrazolyumbromür)] yöntemi kullanılarak Schiff bazlarının, PC3 (insan prostat adenokarsinomu), SHSY-5Y (insan nöroblastomu), A549 (insan akciğer adenokarsinomu), HEK293 (sağlıklı insan embriyonik böbrek hattı) hücre hatları üzerindeki sitotoksik aktivitesi araştırıldı. Bileşiklerin değişen oranlarda aktivite gösterdikleri gözlendi. 2.6 No'lu bileşik yüksek aktivitesi ile öncü molekül olarak belirlendi. Ayrıca bileşiklerin lipofilik karakterleri teorik olarak hesaplanarak aktivite ile ilişkisi incelendi.
Due to the critical role of DNA in replication and transcription mechanisms, it is one of the main targets in the development of antibiotics, anticancer and antiviral drugs. The effects of drugs that bind to DNA in cancer, aids, malaria and many bacterial diseases are known. One of the main challenges in bioorganic chemistry is to synthesize new DNA-targeting compounds as potential anticancer drug leads providing better efficiency with low tissue resistance compared to known complexes such as cisplatin. Schiff bases have been studied for many years because of their high catalytic and biological activities. They are widely used in many fields due to practical synthesis and isolation methods and their affinity for transition metals. Uracil derivatives are considered as an important class of pyrimidines. Uracils with different pharmacological activities such as antitumor, antiallergic and antibacterial are included in the literature. 5-Fluorouracil is used as an anticancer drug. Aminouracil derivatives are used as starting materials for the synthesis of many biologically important uracil compounds. 5-Aminouracil is a remarkable molecule in terms of DNA binding studies due to its ability to form strong hydrogen bonds, its multi-functional structure through lactim-lactam tautomers and functional groups suitable for derivatization. The target molecules of this thesis have been determined according to the results obtained from in silico DNA binding studies of 5-aminouracil derived Schiff bases. Initially, compounds with high DNA binding potential were determined by molecular modeling studies. 5-aminouracil, 5,6-diamino-1,3-dimethyluracil and salicylaldehyde compounds with different functional groups were used as starting materials. At the end of the reactions, 8 new 5-aminouracil derivative Schiff bases and 19 new 5,6-Diamino-1,3-dimethyluracil Schiff bases were synthesized. The precipitated products were filtered off from the reaction medium and obtained pure. The structures of these compounds were determined using FT-IR, 1H-NMR, 13C-NMR and elemental analysis methods. Cytotoxic activity of Schiff bases on PC3 (human prostate adenocarcinoma), SHSY 5Y (human neuroblastoma), A549 (human alveolar adenocarcinoma), HEK293 (human embryonic kidney cells) cell lines was investigated using MTT [3- (4,5-dimethyl-2-thiazoyl)-2,5-diphenyl-2H-tetrazolybromide) method. It was observed that the compounds showed varying degrees of activity on different cell lines. Compound 2.6 was determined as a lead compound with its high activity compared to Doxorubicin on PC3 cell lines. In addition, the lipophilic characters of the compounds were calculated theoretically and their relationship with the activity was examined.
Due to the critical role of DNA in replication and transcription mechanisms, it is one of the main targets in the development of antibiotics, anticancer and antiviral drugs. The effects of drugs that bind to DNA in cancer, aids, malaria and many bacterial diseases are known. One of the main challenges in bioorganic chemistry is to synthesize new DNA-targeting compounds as potential anticancer drug leads providing better efficiency with low tissue resistance compared to known complexes such as cisplatin. Schiff bases have been studied for many years because of their high catalytic and biological activities. They are widely used in many fields due to practical synthesis and isolation methods and their affinity for transition metals. Uracil derivatives are considered as an important class of pyrimidines. Uracils with different pharmacological activities such as antitumor, antiallergic and antibacterial are included in the literature. 5-Fluorouracil is used as an anticancer drug. Aminouracil derivatives are used as starting materials for the synthesis of many biologically important uracil compounds. 5-Aminouracil is a remarkable molecule in terms of DNA binding studies due to its ability to form strong hydrogen bonds, its multi-functional structure through lactim-lactam tautomers and functional groups suitable for derivatization. The target molecules of this thesis have been determined according to the results obtained from in silico DNA binding studies of 5-aminouracil derived Schiff bases. Initially, compounds with high DNA binding potential were determined by molecular modeling studies. 5-aminouracil, 5,6-diamino-1,3-dimethyluracil and salicylaldehyde compounds with different functional groups were used as starting materials. At the end of the reactions, 8 new 5-aminouracil derivative Schiff bases and 19 new 5,6-Diamino-1,3-dimethyluracil Schiff bases were synthesized. The precipitated products were filtered off from the reaction medium and obtained pure. The structures of these compounds were determined using FT-IR, 1H-NMR, 13C-NMR and elemental analysis methods. Cytotoxic activity of Schiff bases on PC3 (human prostate adenocarcinoma), SHSY 5Y (human neuroblastoma), A549 (human alveolar adenocarcinoma), HEK293 (human embryonic kidney cells) cell lines was investigated using MTT [3- (4,5-dimethyl-2-thiazoyl)-2,5-diphenyl-2H-tetrazolybromide) method. It was observed that the compounds showed varying degrees of activity on different cell lines. Compound 2.6 was determined as a lead compound with its high activity compared to Doxorubicin on PC3 cell lines. In addition, the lipophilic characters of the compounds were calculated theoretically and their relationship with the activity was examined.
Açıklama
14.01.2023 tarihine kadar kullanýmý yazar tarafýndan kýsýtlanmýþtýr.
Anahtar Kelimeler
Kimya, Chemistry
