Bir grup Taurultam türevinin sentezi ve karbonik anhidraz inhibitör özelliklerinin değerlendirilmesi
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Dosyalar
Tarih
2018
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Ege Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Diüretik ve antiglokom amaçla tedavide kullanılan 30 adet sülfonamit/sülfamat sınıfı ilacın, KA enzim inhibitör özelliğine sahip olduğu bilinmektedir. Ancak bu bileşiklerin kompakt yapıları, katalitik olarak aktif 13 KA isoenziminin aktif bölgelerindeki aminoasitlerle benzer etkileşimler göstermelerine neden olmaktadır. Selektif olmayan bu inhibisyon, istenmeyen yan etkilerle sonuçlanmaktadır. Bu yüzden, karbonik anhidraz inhibitörü bileşiklerin tasarlanmasında isoenzimlere selektif moleküllerin elde edilmesi amaçlanmaktadır. KA izoenzimlerinden IX’un sadece hipoksik tümör hücrelerinde eksprese olması, spesifik olarak inhibisyonunun mümkün olduğunu göstermektedir. Bu yüzden ilaç geliştirme çalışmalarında önemli bir moleküler hedef haline gelmiştir. Yapılan yapı-aktivite çalışmaları; KA inhibisyonu için aromatik/heterosiklik bir halkaya bağlı primer sülfonamit grubu ile aktif yöredeki çinko iyonunun etkileşmesinin gerekli olduğu saptanmıştır. Selektif izoenzim inhibisyonu ise, bu yapının farklı fizikokimyasal özelliklere sahip zincirlerle türevlendirilmesi sonucunda gerçekleştirilmektedir. Bu ilaç tasarımı kuyruk yaklaşım yöntemi olarak tanımlanmaktadır. Yöntemi önemli kılan ise bu methodun selektif etkili moleküllerin elde edilmesine olanak sağlamasıdır. Çalışmamızda selektif etkiye sahip KA inhibitörü bileşiklerin tasarlanması için, kuyruk yaklaşım yöntemi kullanılmış ve zincir olarak taurultam bileşiği seçilmiştir. Taurultam bileşiği, taurin aminoasitinin türevi ve taurolidin bileşiğinin metabolitidir. Düşük dozlarda antikanser özelliğe sahip olduğu bilinmektedir. Etki mekanizmasının ise; taurinamit gibi metabolitlerinden kaynaklanabileceği bildirilmektedir. Bu bilgiler ışığında, çalışmamızda bir grup taurultam ve açık zincirli bir analoğu sentezlenmiştir. Final ürünlerin yapıları; IR, 1H NMR, APCI-MS, ESI-MS gibi spektroskopik yöntemler ile teyit edilmiştir. Final ürünlerden biri seçilerek, karbonik anhidraz enzim inhibitör etkinliği KA II ve IX izoenzimleri kullanılarak araştırılmıştır. Ayrıca molekülün KA IX izoenzimine gösterdiği selektivite, X-ray difraksiyon yöntemi ile aydınlatılmıştır. Analiz verileri, bileşiğin kanserle-bağlantılı KA IX izoenzimine gösterdiği selektivitenin aktif yörede yaptığı farklı etkileşimlerden kaynaklandığını göstermiştir. Sonuç olarak, proje ile elde edilen veriler ilk defa bu rapor ile bildirilmektedir ve bu sonuçların, kanserle bağlantılı KA IX izoenzimine selektif etkili bileşiklerin tasarımına yön vereceği düşünülmektedir.
It is well known that about 30 sulfonamide/sulfamide type drug which are clinically used for their diuretic and anti-glaucoma effects, show CA inhibitory effect. Though, the compact structure of these CA inhibitors show a non-selective inhibition profile due the fact that their similar interaction with aminoacide residues at the 13 catalytically active region. These limited and similar interactions resulted with a series of side effects that could be prevented by targeting only one isozyme. As a result selective inhibition of isozymes became a challenging factor in the field of CA inhibitor drug development. Among the CA izoenzymes CA IX is known to be expressed only in hipoxic tumour enviroment which makes it to be inhibited spesifically. The structure-activity relationships indicate that a primary sulphonamide group having an organic scaffold is essential for interacting with zinc ion at the active site which is resulted with a strong inhibition. Though, selective inhibition can be achieved by elongation of this scaffold by different substutions which have different physicochemical properties. This modification method is known as “Tail approach”. This is an important methodology as it gives the oppurtinity for achieving selective inhibitors for izozymes. In this study, tail approach was used to design selective CA inhibitors and taurultam was choosen as a tail for derivatizatizion of the organic scafold. Taurultam is a derivative of taurin aminoacid and metobolite of taurolidin. It was reported as an anticancer drug at low doses and this effect was considered to be the result of its tauriamide metobolite. In the light of these data, a group of taurultam derivatives and an open analog of its derivative was synthesized. The structures of the synthesized compounds were established on the basis of IR, 1H NMR, APCI-MS and ESI-MS spectra. One of the synthesized compound was choosen for its inhibitor affinity on CA II and CA IX izozymes. And also X-ray crystallographic studies were conducted for evaluating selectivity of the compound on CA IX over CA II izozyme. The data indicated that additional interactions between the drug and active site of the CA IX izozyme were responsible for compound’s selectivity. As a result, the data obtained from this work are reported for the first time with this report and the results are considered to be useful for designing new selective inhibitors for cancer-related CA IX izozyme.
It is well known that about 30 sulfonamide/sulfamide type drug which are clinically used for their diuretic and anti-glaucoma effects, show CA inhibitory effect. Though, the compact structure of these CA inhibitors show a non-selective inhibition profile due the fact that their similar interaction with aminoacide residues at the 13 catalytically active region. These limited and similar interactions resulted with a series of side effects that could be prevented by targeting only one isozyme. As a result selective inhibition of isozymes became a challenging factor in the field of CA inhibitor drug development. Among the CA izoenzymes CA IX is known to be expressed only in hipoxic tumour enviroment which makes it to be inhibited spesifically. The structure-activity relationships indicate that a primary sulphonamide group having an organic scaffold is essential for interacting with zinc ion at the active site which is resulted with a strong inhibition. Though, selective inhibition can be achieved by elongation of this scaffold by different substutions which have different physicochemical properties. This modification method is known as “Tail approach”. This is an important methodology as it gives the oppurtinity for achieving selective inhibitors for izozymes. In this study, tail approach was used to design selective CA inhibitors and taurultam was choosen as a tail for derivatizatizion of the organic scafold. Taurultam is a derivative of taurin aminoacid and metobolite of taurolidin. It was reported as an anticancer drug at low doses and this effect was considered to be the result of its tauriamide metobolite. In the light of these data, a group of taurultam derivatives and an open analog of its derivative was synthesized. The structures of the synthesized compounds were established on the basis of IR, 1H NMR, APCI-MS and ESI-MS spectra. One of the synthesized compound was choosen for its inhibitor affinity on CA II and CA IX izozymes. And also X-ray crystallographic studies were conducted for evaluating selectivity of the compound on CA IX over CA II izozyme. The data indicated that additional interactions between the drug and active site of the CA IX izozyme were responsible for compound’s selectivity. As a result, the data obtained from this work are reported for the first time with this report and the results are considered to be useful for designing new selective inhibitors for cancer-related CA IX izozyme.
Açıklama
Anahtar Kelimeler
Taurin, Taurultam, Taurinamit Türevleri, Sülfanilamit, Karbonik Anhidraz II, Karbonik Anhidraz IX, Antikanser, Taurine, Taurultam, Taurinamide Derivatives, Sulfanilamide, Carbonic Anhydrase II, Carbonic Anhydrase IX, Anticancer
