Mitokondriyal Hedefli Farklı Nano İskelet Yapılarındaki Yeni Floresans Kaliks[4]Aren-İsatin Bileşiklerinin Sentezi ve Antiproliferatif Özelliklerinin İncelenmesi
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Dosyalar
Tarih
2024
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Yayıncı
Selçuk Üniversitesi, Fen Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Kaliksarenler, fenol ve formaldehitten uygun koşullarda sentezlenen halkalı bileşikler olup, hem fenolik Okonumundan hem de fenolik birimlerin p-konumundan sınırsız olarak fonksiyonlandırılabildiğinden
supramoleküler kimyada ilgi çeken bileşikler olmuşlardır. Son yıllarda kaliks[n]aren türevlerinin kanser
üzerinde önemli bir etkiye sahip olduğu çeşitli çalışmalarla kanıtlanmıştır. İsatin grubu taşıyan bileşiklerin
antidiyabetik, antimikrobiyal, antitüberküloz ve antikanser aktivite çalışmalarında kullanıldığı ve bu
bileşiklerin oldukça geniş bir yelpazede biyolojik etkinlik gösterdikleri gözlenmiştir. Bunlardan Sunitinib,
Nintedanib, Orantinib gibi isatin türevleri preklinik/klinik aşamalarında yer almışlardır. Bu nedenle, bu tez
çalışmasında antikanser aktivite olmak üzere çeşitli biyolojik aktivite ile donatılmış, ümit verici bir yapı
olan ve kanser araştırmalarında yaygın olarak kullanılan isatin türevlerinin araştırılmasına yönelik
çalışmalar yapılmıştır. Bu bağlamda, tez çerçevesinde kaliksaren molekülleri fenolik O-konumundan diazid
türevine dönüştürüldükten sonra p-konumundan 1,4-dimetilpridinyum iyot ile fonksiyonlandırılıp katyonik
ve floresans özellik kazandırıldı. Daha sonra farklı substitute isatin propargil türevleri ile klik reaksiyon
koşullarında etkileştirilerek hedef bileşikler (8a-e) sentezlendi. Katyonik pridinyum biriminin anti-kanser
çalışmalarındaki etkisini araştırmak amacıyla bu grubu taşımayan bileşiklerde sentezlendi (C1-6). Başarı
ile sentezlenen bu bileşikler MCF-7, MDA-MB-231 meme kanseri, A549 akciğer kanseri, HeLa rahim
kanseri, DLD1 kolon kanseri hücre hatlarının yanı sıra sağlıklı epitelyum hücre hattı PNT1A hücrelerinde
sitotoksik etkileri belirlenerek IC50 değerleri hesaplandı ve aynı zamanda floresans görüntüleme çalışmaları
yapıldı. Sentezlenen bileşiğin (8b) mitokondri hedefli olduğunu görmek için HeLa hücresi ile yapılan
lokalizasyon çalışmasında bu bileşiğin hücreye kolaylıkla girdiği ve mitokondride biriktiği gözlendi. Test
edilen kaliksaren türevleri arasından IC50 dozunda en iyi etkiye sahip 8b (IC50: MCF-7;8,83 μM, MDAMB-231;3,32 μM, HeLa;5,23 μM, A549;2,84 μM, DLD1;5,45 μM) altın nanopartiküllere uygun şartlar
altında immobilize edildi ve karakterize edildi. İmmobilizasyon sonucunda 8b-Au’nun IC50 değerleri MCF7; 2,89 μM, MDA-MB-231; 2,87μM olarak hesaplandı. ‘Comet Assay’ ve apoptoz çalışmaları yapıldı.
Yapılan çalışmada, 8b’nin aromataz enzimi üzerinde önemli bir inhibisyon kapasitesi sergiledi (0,104 ±
0,004 uM). Sonuç olarak, katyonik yapıda, mitokondri hedefli floresans kaliks[4]aren-isatin türevleri başta
apoptoz yolağı olmak üzere çeşitli yollarla hücrelerin canlılığını inhibe ettiği gözlend
Calixarenes are cyclic compounds synthesized from phenol and formaldehyde under favorable conditions and are of interest in supramolecular chemistry since they can be functioned infinitely from both the phenolic O-position and the p-position of the phenolic units. It has been proven in recent years that calix[n]arene derivatives have a significant effect on cancer. It has been observed that the compounds carrying isatin groups are used in antidiabetic, antimicrobial, antituberculosis and anticancer activity studies so these compounds have a wide range of biological activity. Isatin derivatives such as Sunitinib, Nintedanib, Orantinib were involved in preclinical/clinical stages. Within the scope of the thesis, calixarene molecules were converted from the phenolic O-position to the diazide derivative and then functionalized with 1,4-dimethylpyridinium iodine from the p-position to give them cationic and fluorescent properties. Then, target compounds (8a-e) were synthesized by interacting isatin with propargyl derivatives with different substitutions under click reaction conditions. In order to investigate the effect of the cationic pyridinium unit in anti-cancer studies, compounds that did not contain this group were synthesized (C1-6). The cytotoxic effects of these successfully synthesized compounds were determined on MCF-7 and MDAMB-231 breast cancer cell lines as well as on epithelial cell line PNT1A cells, IC50 values were calculated, and fluorescence imaging studies were also performed. In the localization study performed with MDAMB-231 cell to see that the synthesized compound (8b) was mitochondria-targeted, it was observed that this compound easily entered the cell and accumulated in the mitochondria. Among the tested calixarene derivatives, 8b (IC50: MCF-7;8.83µM, MDA-MB-231;3.32µM, HeLa;5,23μM, A549;2,84 μM, DLD1;5,45 vi μM) with the best toxicity was immobilized into gold nanoparticles under appropriate conditions and characterized. As a result of immobilization, the toxicity values of 8b-Au were calculated as IC50: MCF7;2.89 µM, MDA-MB-231;2.87µM. 'Comet Assay' and apoptosis studies were carried out. In the study, 8b exhibited a significant inhibition capacity on the aromatase enzyme (0.104 ± 0.004 uM). As a result, it was observed that cationic, mitochondria-targeted fluorescence calix[4]arene-isatin derivatives, inhibited the viability of the cells through various means, especially the apoptosis pathway
Calixarenes are cyclic compounds synthesized from phenol and formaldehyde under favorable conditions and are of interest in supramolecular chemistry since they can be functioned infinitely from both the phenolic O-position and the p-position of the phenolic units. It has been proven in recent years that calix[n]arene derivatives have a significant effect on cancer. It has been observed that the compounds carrying isatin groups are used in antidiabetic, antimicrobial, antituberculosis and anticancer activity studies so these compounds have a wide range of biological activity. Isatin derivatives such as Sunitinib, Nintedanib, Orantinib were involved in preclinical/clinical stages. Within the scope of the thesis, calixarene molecules were converted from the phenolic O-position to the diazide derivative and then functionalized with 1,4-dimethylpyridinium iodine from the p-position to give them cationic and fluorescent properties. Then, target compounds (8a-e) were synthesized by interacting isatin with propargyl derivatives with different substitutions under click reaction conditions. In order to investigate the effect of the cationic pyridinium unit in anti-cancer studies, compounds that did not contain this group were synthesized (C1-6). The cytotoxic effects of these successfully synthesized compounds were determined on MCF-7 and MDAMB-231 breast cancer cell lines as well as on epithelial cell line PNT1A cells, IC50 values were calculated, and fluorescence imaging studies were also performed. In the localization study performed with MDAMB-231 cell to see that the synthesized compound (8b) was mitochondria-targeted, it was observed that this compound easily entered the cell and accumulated in the mitochondria. Among the tested calixarene derivatives, 8b (IC50: MCF-7;8.83µM, MDA-MB-231;3.32µM, HeLa;5,23μM, A549;2,84 μM, DLD1;5,45 vi μM) with the best toxicity was immobilized into gold nanoparticles under appropriate conditions and characterized. As a result of immobilization, the toxicity values of 8b-Au were calculated as IC50: MCF7;2.89 µM, MDA-MB-231;2.87µM. 'Comet Assay' and apoptosis studies were carried out. In the study, 8b exhibited a significant inhibition capacity on the aromatase enzyme (0.104 ± 0.004 uM). As a result, it was observed that cationic, mitochondria-targeted fluorescence calix[4]arene-isatin derivatives, inhibited the viability of the cells through various means, especially the apoptosis pathway
Açıklama
Anahtar Kelimeler
Antikanser Aktivite, Enzim İnhibisyon, İsatin, Kaliks[4]aren, Mitokondri Hedefli, Anticancer Activity, Calix[4]arene, Enzyme Inhibition, Isatin, Mitochondria Targeted
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Künye
Oğuz A., (2024). Mitokondriyal Hedefli Farklı Nano İskelet Yapılarındaki Yeni Floresans Kaliks[4]Aren-İsatin Bileşiklerinin Sentezi ve Antiproliferatif Özelliklerinin İncelenmesi. (Doktora Tezi). Selçuk Üniversitesi, Fen Bilimleri Enstitüsü, Konya.
