Synthesis and radioiodination of aniline-mustard-glucuronide and test of its anticancer potential
Küçük Resim Yok
Tarih
2000
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Yayıncı
Ege Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
V ÖZET ANİLİN-MÜSTARD-GLUKURONİD'İN SENTEZİ RADYOAKTİF 131I İLE İŞARETLENMESİ VE ANTİKANSER İLAÇ POTANSİYELİNİN İNCELENMESİ AKGÜN, Zeynep Yüksek Lisans Tezi, Kimya Anabilim Dalı Danışman : Prof. Dr. Turan ÜNAK Şubat 2000, 108 sayfa. Bu çalışmanın temel amacı, radyoterapik ve kemoterapik etkilerin bir araya geldiği antikanser bir ilacın tasarlanmasıdır. Bu amaçla, antikanser bir ajan olarak anilin-mustard seçilmiştir. Anilin- mustardın antikanser özelliği, onun DNA ile çapraz bağlanma yapabilmesinden kaynaklanmaktadır. Aynı zamanda, anilin-mustardın literatürde bazı kanser hücrelerinde seçimli olarak birikim yapabildiği de kayıtlıdır. Anilin-mustardın bu seçimli olarak birikim gösterebilme özelliği ise, bazı kanser türlerinde fazla olarak bulunabilen |3- glukuronidaz enziminin varlığı ile açıklanmaktadır. Buna göre, anilin- mustard ilk olarak karaciğerde bir hidroksilaz enzimi ile hidroksillenir, daha sonra da, UDP-glukoziltransferaz enzimi ile de glukuronid türevi haline dönüştürülür. Öte yandan, literatürede yüksek LET değerine sahip radyasyonlar salan radyonüklidlerin canlı sistemler üzerinde yüksek bir radyotoksik etkiye sahip olduğu kayıtlıdır. Alfa radyasyonları ile Auger electronlan genel olarak yüksek LET değerine sahip olan radyasyonlar kategorisinde yer almaktadırlar. Bu da, etkin alfa ve/veya Auger elektronu salan radyonüklidlerin yüksek radyotoksikVI etkiye sahip radyonüklidler olduğu anlamını taşımaktadır. Özellikle çok kısa menzile sahip olan bu radyasyonlar radyotoksik etkinin çok kuçuk bir bölge içinde sınırlı kalmasına neden olmaktadır. Bunun anlamı da, radyotosik etkinliğin yalnızca radyonuklidin bozunma bölgesi ile sınırlı kalmasıdır. Bu tür bir radyonuklidin bir kanser hücresinin çekirdeği içinde, özellikle de DNA yapısında veya DNA'ya çok yakın bir bölgede bozunması halinde, bu kanser hücresinin çok ciddi bir hasar göreceği muhakkaktır. Bu yüzden, yüksek LET değerli radyasyonlar salan radyonüklidler de, kanser radyoterapisinde geniş bir uygulama alanına sahip bulunmaktadırlar. n\ I, 211At ve benzeri bazı radyonüklidler yüksek radyotoksisiteye sahip olan bu radyonüklidler kategorisinde yer alırlar. Bu çalışmada, anilin-mustard literatürde verilen şartlar uygulanarak sentez edilmiş ve onun glucuronid türevi ise, ağızdan anilin-mustard verilen bir tavşanın idrarından metabolik yolla eldilmiştir. Daha sonra, anilin-mustard ve onun metabolik glukuronid türevi radyoaktif iyodogen yöntemi kullanılarak 131I ile işretlenmiştir. Böylece, bu bileşiklerin diğer radyoaktif iyod izotopları ve hatta bir başka halojen olan 211At ile işretlenebilmesi imkanı ortaya konmuş bulunmaktadır. Sonuç olarak da, anilin-mustard ve onun metabolik glukuronid türevinin literatürde ilk kez radyoiyodinasyonu gerçekleştirilmiş olmaktadır. Radyoiyodinasyonu yapılmış olan bu maddelerin ilk metabolik testleri de tavşanlar üzerinde yapılmıştır. Bunun için, kulak damarlarından bu maddelerin injeksiyonu yapılan tavşanların dinamik sintigramlan alınmıştır. Bu sintigrafik incelemeler anilin-mustardın aşağı-yukan 15 dakikalık bir süre içinde süratle metabolizmadan temizlenerek mesaneye geçtiğini göstermiştir. Bu temizlenme zamanının, anilin-mustardın metabolik glukuronid türevi için 45 dakika dolayında olduğu da bulunmuştur. Radyoiyodinasyonu yapılan anilin-mustardın vücût organlarındaki daha detaylı dağılımlarının zamanla değişimleri de, sıçanlar üzerinde denenmiştir. Bu vücut dağılımlarından elde edilenvn sonuçlar da, anilin-mustard He onun «etabolik glukuronid türevinin arasındaki ilginç farklılığı açıkça ortaya çıkarmıştır. Bu ilginç farklılıklardan birisi de karaciğerde gözlenmiştir. -Karaciğerdeki anilin-mustard aktivitesinin zaman içinde hafifçe artış göstermesine karşın, bunun metabolik glukuronid -türevinin -hafifçe -bir azalış gösterdiği tespit edilmiştir. Bu da, anilin-mustard ile onun metabolik glukuronid türevi arasındaki drug-prodrug ilişkisini açıkça ortaya koymaktadır. Diğer ilginç bir sonuç da, pankreasta gözlenmiştir. Bu organdaki her iki maddeye ilişkin aktivite birikimi ise % 20 - 25 olacak kadar yüksek bulunmuş, ancak bunun 24 saatlik sure içinde pratikçe temizlendiği gözlenmiştir. Midedeki aktivite birikimi anilin- mustard durumunda % 30'lara varan bir ölçüde yüksek bulunuşken, bu miktar metabolik glukuronid türevi için yalnızca % 6'lar civarında kalmıştır. Sıçanlar üzerindeki bu vücut dağılım çalışmalarından elde edilen sonuçlar da, bu ikin maddenin metabolik karakterlerinin farklılığını açıkça ortaya koymuştur. Butun bu sonuçlar, bazı kanser hücreleri içinde gerçekten seçimli olarak birikim gösterdiğinin kanıtlanması durumunda, aniline- mustardm glukuronid türevinin radyoiyodinasyonu yapılan bir prodrug olarak kullamlabileceğini ortaya koymaktadır. Bu yüzden, bu çalışmanın gelecek aşamalarında, anilin-mustard ve onun glukuronid türevinin drug-prodrug sistemi olarak tümör oluşturulacak laboratuvar hayvanları veya doku kültürü ile üretilecek kanser iıücreieri üzerinde test edilmesi hedeflenecektir. Anahtar kelimeler : Anilm-mustard,^-glukuromdaz, urüm-mustard- glucuronid, radyoiyodinasyon, iyod-131, iyod-125, iodogen, glukuronid
IX ABSTRACT SYNTHESIS AND RADIOIODINATION OF ANILINE-MUSTARD-GLUCURONIDE AND TEST OF ITS ANTICANCER POTENTIAL AKGÜN, Zeynep M. Sain Chemistry Supervisor: Turan ÜNAK, Ph. D., Professor of Nuclear Chemistry February 2000, 108 pages The principal aim of this study was design a radiolabeled anticancer prodrug for combining chemo- and radio-therapy of cancer. For this purpose, aniline-mustard has been chosen as a model anticancer agent. The anticancer potential of aniline-mustard is originated from the DNA alkylating potential of nitrogen-mustard derivatives. Aniline-mustard was also reported in the literature as a chemo-therapeutic agent which has a selectively accumulation potential in some kind of tumor cells. This selective accumulation potential of aniline-mustard has been explained by the high 0- glucuronidase activity, as an enzyme which are rich in some kind of tumor cells. According to this concept, aniline-mustard is first hydroxylated in liver by an hydroxylase, and then glucuronidated by UDP-glucosyhransferanse for its rapid detoxification and excretion from the metabolism.On the other hand, it is reported in the literature that the radionuclides which emit high LET radiations cause high level radiotoxicity in living systems. Alpha-radiations and Auger electrons are generally in the top list of high LET radiations category. Thus, effective Auger and/or alpha-radiation emitters are generally high radiotoxic radionuclides. Significantly very short ranges of these radiations causes to be localized their radiotoxic effectiveness. This means that their high radiotoxic effectiveness are only valid in the near vicinity of the radionuclide decayed. In the case of the radionuclide decay occurs in the nucleus of a cancer cell, particularly in the structure of DNA or close to it, this cell should be very seriously damaged following the decay of this radionuclide. Consequently, high LET radiation emitter radionuclides, too, have a large potential applications in cancer radio-therapy. 123L, 125L 211At, and some others are the radionuclides considered in the category of high radiotoxic radionuclides. In this study, aniline-mustard was synthesized according to the chemical procedures given in the literature, and its glucuronide conjugate has been also obtained by the metabolic method as being crystallized from the urine of a rabbit to whom aniline-mustard was orally administrated, and then aniline-mustard and its glucuronide conjugate were radioiodinated with 131I using the iodogen method. Thus, their radioiodinations with other radioiodine isotopes, and also with probably 211 At as an other halogen radionuclide were proven. So,XI aniline-mustard and its glucuronide conjugate as being drug-prodrug system were firstly radioiodinated in the literature. The preliminary metabolic tests of these radioiodinated materials were carried out on rabbits. For these tests dynamic scintigrams of rabbits to whom radioiodated aniline-mustard and its glucuronide conjugate were separately injected via their ear veins. These scintigrams clearly showed that glucuronide conjugate of aniline-mustard was very quickly cleared from the metabolism accumulating in the bladder in about 15 m. This clearance time of radioiodinated aniline-mustard was considerably longer as being about 45 m. This is good accordance with the drug-prodrug relation between aniline-mustard and its glucuronide conjugate. The biodistribution of the radioiodated aniline-mustard and its glucuronide conjugate in principal organs of rats were measured as a function of time. The results obtained from these biodistributional studies have also represented interesting differences between the metabolic details of radioiodinated aniline-mustard and its glucuronide conjugate. One of the interesting differences is observed on liver. The radioiodine activity observed in liver as a function of time slightly increased in the case of aniline-mustard, but contrarily decreased in the case of its glucuronide conjugate. This also clearly reflects the drug-prodrug relation between aniline-mustard and its glucuronide conjugate. Another significant result was observed onxn pancreas; this organ has shown a considerable radioiodine activity following the injections of radioiodinated material as being 20-25 % of the total organs activity, and in both cases the radioiodine activities in these organs were practically cleared in 24 h. It is also very significant that in the case of glucuronide conjugate of aniline- mustard, the accumulation of radioiodine activity in stomach was very high as being the mean activity value about 30 %. In the case of aniline-mustard the same value was about only 6 %. Briefly, the biodistributions of radioiodinated aniline-mustard and its glucuronide conjugate in different principal organs of rats clearly indicate the difference between metabolic character of radioiodinated aniline- mustard and its glucuronide conjugate. All these results promise to be used the radioiodinated glucuronide conjugate of aniline-mustard as an appropriate radioiodinated prodrug, in the case of really verification of its selectively accumulation in some kind of tumor cells. For this reason, as the next step of this study this radioiodinated drug-prodrug system should eventually be tested on the tumor bearing laboratory animals or on the specific tumor cells produced by tissue culture studies. Keywords: Aniline-mustard, ^-glucuronidase, radiolabeling, 131I, iodogen, glucuronide.
IX ABSTRACT SYNTHESIS AND RADIOIODINATION OF ANILINE-MUSTARD-GLUCURONIDE AND TEST OF ITS ANTICANCER POTENTIAL AKGÜN, Zeynep M. Sain Chemistry Supervisor: Turan ÜNAK, Ph. D., Professor of Nuclear Chemistry February 2000, 108 pages The principal aim of this study was design a radiolabeled anticancer prodrug for combining chemo- and radio-therapy of cancer. For this purpose, aniline-mustard has been chosen as a model anticancer agent. The anticancer potential of aniline-mustard is originated from the DNA alkylating potential of nitrogen-mustard derivatives. Aniline-mustard was also reported in the literature as a chemo-therapeutic agent which has a selectively accumulation potential in some kind of tumor cells. This selective accumulation potential of aniline-mustard has been explained by the high 0- glucuronidase activity, as an enzyme which are rich in some kind of tumor cells. According to this concept, aniline-mustard is first hydroxylated in liver by an hydroxylase, and then glucuronidated by UDP-glucosyhransferanse for its rapid detoxification and excretion from the metabolism.On the other hand, it is reported in the literature that the radionuclides which emit high LET radiations cause high level radiotoxicity in living systems. Alpha-radiations and Auger electrons are generally in the top list of high LET radiations category. Thus, effective Auger and/or alpha-radiation emitters are generally high radiotoxic radionuclides. Significantly very short ranges of these radiations causes to be localized their radiotoxic effectiveness. This means that their high radiotoxic effectiveness are only valid in the near vicinity of the radionuclide decayed. In the case of the radionuclide decay occurs in the nucleus of a cancer cell, particularly in the structure of DNA or close to it, this cell should be very seriously damaged following the decay of this radionuclide. Consequently, high LET radiation emitter radionuclides, too, have a large potential applications in cancer radio-therapy. 123L, 125L 211At, and some others are the radionuclides considered in the category of high radiotoxic radionuclides. In this study, aniline-mustard was synthesized according to the chemical procedures given in the literature, and its glucuronide conjugate has been also obtained by the metabolic method as being crystallized from the urine of a rabbit to whom aniline-mustard was orally administrated, and then aniline-mustard and its glucuronide conjugate were radioiodinated with 131I using the iodogen method. Thus, their radioiodinations with other radioiodine isotopes, and also with probably 211 At as an other halogen radionuclide were proven. So,XI aniline-mustard and its glucuronide conjugate as being drug-prodrug system were firstly radioiodinated in the literature. The preliminary metabolic tests of these radioiodinated materials were carried out on rabbits. For these tests dynamic scintigrams of rabbits to whom radioiodated aniline-mustard and its glucuronide conjugate were separately injected via their ear veins. These scintigrams clearly showed that glucuronide conjugate of aniline-mustard was very quickly cleared from the metabolism accumulating in the bladder in about 15 m. This clearance time of radioiodinated aniline-mustard was considerably longer as being about 45 m. This is good accordance with the drug-prodrug relation between aniline-mustard and its glucuronide conjugate. The biodistribution of the radioiodated aniline-mustard and its glucuronide conjugate in principal organs of rats were measured as a function of time. The results obtained from these biodistributional studies have also represented interesting differences between the metabolic details of radioiodinated aniline-mustard and its glucuronide conjugate. One of the interesting differences is observed on liver. The radioiodine activity observed in liver as a function of time slightly increased in the case of aniline-mustard, but contrarily decreased in the case of its glucuronide conjugate. This also clearly reflects the drug-prodrug relation between aniline-mustard and its glucuronide conjugate. Another significant result was observed onxn pancreas; this organ has shown a considerable radioiodine activity following the injections of radioiodinated material as being 20-25 % of the total organs activity, and in both cases the radioiodine activities in these organs were practically cleared in 24 h. It is also very significant that in the case of glucuronide conjugate of aniline- mustard, the accumulation of radioiodine activity in stomach was very high as being the mean activity value about 30 %. In the case of aniline-mustard the same value was about only 6 %. Briefly, the biodistributions of radioiodinated aniline-mustard and its glucuronide conjugate in different principal organs of rats clearly indicate the difference between metabolic character of radioiodinated aniline- mustard and its glucuronide conjugate. All these results promise to be used the radioiodinated glucuronide conjugate of aniline-mustard as an appropriate radioiodinated prodrug, in the case of really verification of its selectively accumulation in some kind of tumor cells. For this reason, as the next step of this study this radioiodinated drug-prodrug system should eventually be tested on the tumor bearing laboratory animals or on the specific tumor cells produced by tissue culture studies. Keywords: Aniline-mustard, ^-glucuronidase, radiolabeling, 131I, iodogen, glucuronide.
Açıklama
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Anahtar Kelimeler
Kimya, Chemistry, Anilin-mustard-glukuronid, Aniline-mustard-glucuronide, Glukuronid, Glucuronide, Neoplazmlar, Neoplasms, Radyoaktif izleyiciler, Radioactive tracers, İlaç tedavisi, Drug therapy
