Mitokondriyal hedefli farklı yapılardaki yeni floresans kaliks[4]aren-benzimidazol bileşiklerinin sentezi ve farklı kanser hücre hatlarında antikanser özelliklerinin incelenmesi
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Tarih
2024
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Selçuk Üniversitesi, Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Kanser; agresifliği, yüksek prevalansı ve etkili tedavi eksikliği nedeniyle dünyada ölüm nedenleri sıralamasında, kalp ve damar hastalıkların hemen ardından gelmektedir. Kemoterapi, radyasyon tedavisi, hedefe yönelik tedavi, immünoterapi ve cerrahi yöntemler kanser hastalarının prognozunu önemli ölçüde geliştirmiştir. Ancak yan etkiler klinikte hala çözülmesi gereken bir sorundur. Kaliksaren'in farmasötik endüstrilerinde nanobasket olarak uygulanması, istenen yüzey modifikasyonu, biyouyumluluk ve üstün kararlılığı nedeniyle büyük ilgi çekmiştir. Ayrıca, farklı gruplarla modifiye edilmiş kaliksarenler kanser hücreleriyle kolaylıkla etkileşebilir çünkü bu bileşiklerin yapısında hidrofobik ve hidrofilik kısımlar bulunmaktadır. Bu bileşiklere gerekli fonksiyonel gruplar bağlandığında tümör dokularını hedefleme potansiyeline sahip olabilmektedir. Kaliks[n]aren türevli bileşikler, antikarsinojen veya ilaç taşınımı gibi özelliklere sahip olması, yeni türevlerinin sentezinin kanser tedavisinde alternatif bir kullanım olabileceği düşünülmektedir. Son yıllarda keşfedilen antikanser ilaçlar arasında benzimidazoller de yer almıştır. Benzimidazol bileşikleri antidiyabetik, antimikrobiyal, antitüberküloz ve antikanser aktivite çalışmalarında kullanıldığı ve bu bileşiklerin oldukça geniş bir yelpazede biyolojik etkinlik gösterdikleri gözlenmiştir. Bu bileşikler uygun gruplarla fonksiyonlandırıldığında floresans özellik gösterebilmelerinden dolayı hücre-içi çalışmaları yapılabilmektedir. Çalışmamızın amacı, yeni kaliks[4]aren-benzimidazol türevlerini dört farklı kanser hücre hattında hücre proliferasyonu, apoptoz, floresans ölçümü ve hücre görütüntüleme çalışmaları yaparak bu bileşiklerin anti-kanser etkilerinin ortaya konulmasıdır. Bu amaçla çalışmada; potansiyel anti-kanser ajan olabilecek çeşitli fonksiyonel gruplara sahip floresans ışıma yapan yeni kaliks[4]aren-benzimidazol türevleri sentezlendi. Karşılaştırma amacıyla diestere benzimidazol türevi bağlanarak sentezlendi. Bunlara ilaveten hücre kültürü çalışmaları; MCF-7, HELA ve HT-29 hücre hatlarında hücre proliferasyonuna ve apoptoza etkileri ortaya konuldu. HEK-293 insan embriyonik böbrek hücre hattında üzerinde bileşiklerin düşük sitotoksiteye sahip olduğu görüldü. Sentezlenen bileşiklerin katyonik yapılarından dolayı, negatif yüklü mitokondri membranını hedeflediği farklı kanser hücrelerinde konfokal mikroskobuyla görüntülenerek kanıtlandı. Çalışmamızda yeni kaliks[4]aren-benzimidazol türevleri (5b-d bileşikleri ve 5e) sentezlendi. Sentezlenen bu bileşiklerin yapısı FT-IR ve 1H-NMR tekniği ile aydınlatıldı. Bu bileşiklerin (5b-d) floresans özellikleri UV-vis. ve Floresans spektroskobisi kullanılarak incelendi. 5b-d bileşiklerinin sitotoksik etkileri belirlenen doz (5-100 μM aralığında) ve zaman (24 ve 48 saat) aralıklarında farklı kanser hücre hatlarında MTT yöntemiyle araştırıldı. 24 ve 48. saatte IC50 değerleri hesaplandı. Bu hesaplamalar sonucunda 24. saatte 5c bileşiğinin HT-29 hücre hattında (15,9 μM), HELA hücre hattında (22,48 μM), 5d bileşiğinin HELA hücre hattında (20,04 μM) en düşük dozda etkin sitotoksite gözlendi. Hücre ölüm mekanizmasını incelemek amacıyla Annexin V yöntemi ile apoptoz analizi yapıldı. Belirlenen IC50 değerleri ile yapılan apoptoz analizi sonucunda, total apoptoz yüzdeleri; 5b bileşiğinin 24. saatteki HELA hücre hattında, HELA kontrol grubu hücrelerine göre canlılığı %47,76'ya, HT-29 hücre hattında 48. saatte kontrol grubuna göre canlılığı % 53,82'ye, 5c bileşiğinin 24. saatteki HT-29 hücre hattında kontrol grubuna göre canlılığı % 54,94'e, 5d bileşiğinin 48. saatteki MCF-7 hücre hattında kontrol grubuna göre canlılığı %55,71'e düşürerek proliferasyonu inhibe etmiştir. Bu üç bileşiğin üç farklı kanser hücre hattında 24. ve 48. saatte belirlenen IC50 değerleri HEK-293 hücre hattında uygulandığında % canlılık değerleri sırasıyla; MCF-7 hücre hattının dozunda %87,04-%98,45 aralığında, HT-29 hücre hattının dozunda %79,29-%90,28 aralığında, HELA hücre hattının dozunda HEK-293'te %78,88-%100,00 aralığında bulundu. "Elde ettiğimiz bu sonuçlar doğrultusunda yeni kaliks[4]aren-benzimidazol türevlerinin ileride bu konuda yapılacak olan antikanser terapötik ilaç araştırmalara temel teşkil edeceği ortaya konuldu.
Cancer; due to its aggressiveness, high prevalence and lack of effective treatment, it comes right after cardiovascular diseases in the list of causes of death in the world. Chemotherapy, radiation therapy, targeted therapy, immunotherapy and surgery have significantly improved the prognosis of cancer patients. However, side effects are a problem that still needs to be solved in the clinic. The application of calixarene as nanobasket in pharmaceutical industries has attracted much attention due to its desired surface modification, biocompatibility and superior stability. In addition, calixarenes modified with different groups can easily interact with cancer cells because these compounds have hydrophobic and hydrophilic parts in their structure. When the necessary functional groups are attached to these compounds, they may have the potential to target tumor tissues. Since calix[n]arene-derived compounds have properties such as anticarcinogenic or drug transport, it is thought that the synthesis of new derivatives may be an alternative use in cancer treatment. Benzimidazoles are among the anticancer drugs discovered in recent years. Benzimidazole compounds have been used in antidiabetic, antimicrobial, antituberculosis and anticancer activity studies, and it has been observed that these compounds show a wide range of biological activities. Since these compounds exhibit fluorescence properties when functionalized with appropriate groups, intracellular studies can be performed. The aim of our study is to reveal the anti-cancer effects of new calix[4]arene-benzimidazole derivatives by performing cell proliferation, apoptosis, fluorescence measurement and cell imaging studies on four different cancer cell lines. For this purpose; The new Calix [4] Aren-Benzimidazole derivatives were synthesized by potential anti-cancer agent. For the comparison, the diestere benzimidazole derivative was synthesized by connecting. In addition, cell culture studies; MCF-7, HELA and HT-29 cell lines were revealed on cell proliferation and apoptosis. Hek-293 Human embryonic kidney cell line was found to have low cytotoxide compounds on the cell line. Due to the cationic structures of synthesized compounds, the negatively charged mitochondria membrane was proved by displaying with a confocal microscope in different cancer cells. In our study, the new Calixs [4] were synthesized by Aren-Benzimidazole derivatives (5B-D compounds and 5E). The structure of these synthesized compounds was illuminated by FT-IR and 1H-NMR technique. Fluorescence properties of these compounds (5B-D) UV-Vis. and fluorescence spectroscopy. The cytotoxic effects of 5B-D compounds were investigated by MTT method on different cancer cell lines at the determined dose (5-100 μm range) and time (24 and 48 hours) intervals. IC50 values were calculated at 24 and 48 hours. As a result of these calculations, active cytotoxite was observed in the HT-29 cell line (15.9 μm) of the 5C compound at 24 hours, on the Hela cell line (22.48 μm) and the 5D compound was observed at the lowest dose (20,04 μm) on the Hela cell line (20.04 μm). In order to examine the cell death mechanism, apoptosis was performed with Annexin V method. As a result of apoptosis analysis with identified IC50 values, total apoptosis percentages; 5B compound 24. On the 24th hour, the viability compared to the Hela control group cells is 47.76 % compared to the cell line, HT-29 cell line 48. Viability compared to the control group at 53.82 %, 5C compound 24. The viability in the line compared to the control group inhibited proliferation by decreasing the viability to 54.94 % and the viability of the 5D compound to 55.71 % compared to the control group on the MCF-7 cell line at the 48th hour. When the IC50 values determined at the 24th and 48th hour on the three different cancer cell lines of these three compounds are applied on the hek-293 cell line, % vitality values are; 87.04-98.45 %at the dose of MCF-7 cell line, 79.29-90 %at the dose of the HT-29 cell line, 78.88-93 %at the dose of the Hela cell line 78.88-100 %at the dose of the cell line found in the range. In line with these results, it was revealed that new calix[4]arene-benzimidazole derivatives will form the basis for future anticancer therapeutic drug research on this subject.
Cancer; due to its aggressiveness, high prevalence and lack of effective treatment, it comes right after cardiovascular diseases in the list of causes of death in the world. Chemotherapy, radiation therapy, targeted therapy, immunotherapy and surgery have significantly improved the prognosis of cancer patients. However, side effects are a problem that still needs to be solved in the clinic. The application of calixarene as nanobasket in pharmaceutical industries has attracted much attention due to its desired surface modification, biocompatibility and superior stability. In addition, calixarenes modified with different groups can easily interact with cancer cells because these compounds have hydrophobic and hydrophilic parts in their structure. When the necessary functional groups are attached to these compounds, they may have the potential to target tumor tissues. Since calix[n]arene-derived compounds have properties such as anticarcinogenic or drug transport, it is thought that the synthesis of new derivatives may be an alternative use in cancer treatment. Benzimidazoles are among the anticancer drugs discovered in recent years. Benzimidazole compounds have been used in antidiabetic, antimicrobial, antituberculosis and anticancer activity studies, and it has been observed that these compounds show a wide range of biological activities. Since these compounds exhibit fluorescence properties when functionalized with appropriate groups, intracellular studies can be performed. The aim of our study is to reveal the anti-cancer effects of new calix[4]arene-benzimidazole derivatives by performing cell proliferation, apoptosis, fluorescence measurement and cell imaging studies on four different cancer cell lines. For this purpose; The new Calix [4] Aren-Benzimidazole derivatives were synthesized by potential anti-cancer agent. For the comparison, the diestere benzimidazole derivative was synthesized by connecting. In addition, cell culture studies; MCF-7, HELA and HT-29 cell lines were revealed on cell proliferation and apoptosis. Hek-293 Human embryonic kidney cell line was found to have low cytotoxide compounds on the cell line. Due to the cationic structures of synthesized compounds, the negatively charged mitochondria membrane was proved by displaying with a confocal microscope in different cancer cells. In our study, the new Calixs [4] were synthesized by Aren-Benzimidazole derivatives (5B-D compounds and 5E). The structure of these synthesized compounds was illuminated by FT-IR and 1H-NMR technique. Fluorescence properties of these compounds (5B-D) UV-Vis. and fluorescence spectroscopy. The cytotoxic effects of 5B-D compounds were investigated by MTT method on different cancer cell lines at the determined dose (5-100 μm range) and time (24 and 48 hours) intervals. IC50 values were calculated at 24 and 48 hours. As a result of these calculations, active cytotoxite was observed in the HT-29 cell line (15.9 μm) of the 5C compound at 24 hours, on the Hela cell line (22.48 μm) and the 5D compound was observed at the lowest dose (20,04 μm) on the Hela cell line (20.04 μm). In order to examine the cell death mechanism, apoptosis was performed with Annexin V method. As a result of apoptosis analysis with identified IC50 values, total apoptosis percentages; 5B compound 24. On the 24th hour, the viability compared to the Hela control group cells is 47.76 % compared to the cell line, HT-29 cell line 48. Viability compared to the control group at 53.82 %, 5C compound 24. The viability in the line compared to the control group inhibited proliferation by decreasing the viability to 54.94 % and the viability of the 5D compound to 55.71 % compared to the control group on the MCF-7 cell line at the 48th hour. When the IC50 values determined at the 24th and 48th hour on the three different cancer cell lines of these three compounds are applied on the hek-293 cell line, % vitality values are; 87.04-98.45 %at the dose of MCF-7 cell line, 79.29-90 %at the dose of the HT-29 cell line, 78.88-93 %at the dose of the Hela cell line 78.88-100 %at the dose of the cell line found in the range. In line with these results, it was revealed that new calix[4]arene-benzimidazole derivatives will form the basis for future anticancer therapeutic drug research on this subject.
Açıklama
Anahtar Kelimeler
Apoptoz, Antikanser Etki, Benzimidazol, Hücre Hattı, Kaliks[4]aren, Proliferasyon, Apoptosis, Anticancer Effect, Benzimidazole, Calix[4]arene, Cell Line, Proliferation
Kaynak
WoS Q Değeri
Scopus Q Değeri
Cilt
Sayı
Künye
Solmaz, B. (2024). Mitokondriyal hedefli farklı yapılardaki yeni floresans kaliks[4]aren-benzimidazol bileşiklerinin sentezi ve farklı kanser hücre hatlarında antikanser özelliklerinin incelenmesi. (Yüksek Lisans Tezi). Selçuk Üniversitesi, Sağlık Bilimleri Enstitüsü, Konya.
