Kinoksalin ligantları içeren yeni antıtumor aktif bakır ve platin temelli komplekslerin tasarımı, sentezi ve biyolojik aktiviteleri
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Date
2022
Authors
Özalp Yaman, Şeniz
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Abstract
Bugün dünya genelinde kanser en önde gelen ölüm sebebidir. Bu nedenle biyotıp ve sağlık bilimlerinde daha iyi ve güncel antineoplastik ajanlar geliştirilmesi büyük bir önem taşımaktadır. Metal temelli ilaçların kanserle savaşmak için yüksek bir potansiyele sahip olduğu bilinmektedir. Elde edilen verilerin ışığında yapılan bu araştırma ön ilaç adayı olarak (2,3-di-piridin-2-il-kinoksalin) (dpq), (2,3-di-tiyenyl-2-il-kinoksalin) (dtq), (2,3,2',3'-tetra-piridin-2-il-[6,6']bikinoksalin) (tpbq) ve (2,3,2',3'-tetra-tiyenyl-2-il-[6,6']bikinoksalin) içeren bakır(II)/platin(II) bileşiklerinin sentezi ve antikanser aktivitelerini hedeflemektedir. Sentezlenen bileşiklerin buzağı timus DNA'sı (CT-DNA) ve insan serum albümini (HSA) ile bağlanma etkileşimleri UV titrasyonu, termal bozunma, viskometrik ve florometrik ölçümlerle değerlendirilmiştir. Yapılan çalışmalar sonucunda Pt(tpbq)Cl2, Pt(ttbq)Cl2 ve Cu(tpbq)Cl2 dışında sentezlenen tüm komplekslerin CT-DNA'ya elektrostatik etkileşim ile bağlandığı, bu etkileşimin komplekslerde yer alan oynak klor iyonlarının yapıdan uzaklaşması ile oluşan kompleks katyon ile CT-DNA'nın negatif fosfat grupları arasındaki elektrostatik çekimden kaynaklanabileceği öngörülmüştür. Pt(tpbq)Cl2, Pt(ttbq)Cl, ve Cu(tpbq)Cl2 komplekslerinin ise CT-DNA ile van der Waals ve hydrogen bağı oluşturduğu sonucuna varılmıştır. Ayrıca, komplekslerin HSA'nın higroskopik bölgesine tutunduğu gözlenmiştir. Komplekslerin antitümör aktiviteleri, insan glioblastoma A172, LN229 ve U87 hücre hatları, insan akciğer A549, insan meme MDA-231, insan serviks HeLa ve insan prostat PC-3 hücre hatlarında çalışılmıştır. Hücre canlılığı (MTT), oksidatif stres, apoptoz –TUNAL, in vitro-hücre göç ve istila, in vitro-Komet DNA hasar ve plazmit DNA etkileşim testleri gerçekleştirilmiştir. Sürdürülen çalışmalar sonucunda U87 ve HeLa hücreleri, komplekslerimize en duyarlı kanser hücreleri olarak belirlenmiştir. Komplekslerin sitotoksik etkilerinin bu hücre hatlarında meydana getirdikleri reaktif oksijen türlerinin oluşumudan kaynaklandığı ve Cu(dtq)2Cl2, Cu(ttbq)Cl2, Pt(ttbq)Cl2 ve Pt(tpbq)Cl2'nin test edilen kompleksler arasında apoptoz yoluyla en yüksek DNA degradasyonu potansiyeline ve antikanser etkisine sahip olduğu gösterilmiştir. Yara iyileşmesi ve istila analizi sonuçları da bu kompleklserin yüksek antikanser aktivitesini destekler niteliktedir.
Across the globe, today, cancer accounts for many fatalities, thus calling for better and updated antineoplastic agents within biomedicine and health sciences. In this regard, inorganic chemistry for pharmaceutic purposes is essential in creating drugs based in metal to fight cancer as such medicine has been shown to be potentially effective to fight cancer in humans. In light of this background, this research focuses on synthesis and anticancer activity of (2,3-di-pyridin-2-yl-quinoxaline), (2,3-di-thenyl-2-yl-quinoxaline), (2,3,2',3'-tetra-pyridin-2-yl-[6,6']biquinoxaline) and (2,3,2',3'-tetra-thenyl-2-yl-[6,6']biquinoxaline) containing copper(II) and platinum(II) compounds as prodrug candidates. The binding interaction of these compounds with calf thymus DNA (CT-DNA) and human serum albumin (HSA) of the complexes were assessed with UV titration, thermal decomposition, viscometric, and fluorometric measurements. The nature of the binding of the complexes on DNA were revealed as electrostatic interaction between the cationic metal complex ions and the negative phosphate groups of CT-DNA upon removal of one or two labile chloride ion(s), except Pt(tpbq)Cl2, Pt(ttbq)Cl2, and Cu(tpbq)Cl2; van der Waals and hydrogen bonds interaction were proposed for these complexes. In addition, our complexes induced a surface contact through the hygroscopic region of serum albumin. Antitumor activity of the complexes against human glioblastoma A172, LN229, and U87 cell lines and human lung A549, human breast MDA-231, human cervix HeLa, and human prostate PC-3 cell lines were investigated by examining cell viability (MTT), oxidative stress, apoptosis-TUNEL, in vitro migration an invasion, in vitro-Comet DNA demage, and plasmid DNA interaction assays. The U87 and HeLa cells were investigated as the cancer cells most sensitive to our complexes. The exerted cytotoxic effect of complexes was attributed to the formation of the reactive oxygen species in vitro. It is clearly demonstrated that Cu(dtq)2Cl2, Cu(ttbq)Cl2, Pt(ttbq)Cl2 and Pt(tpbq)Cl2 have the highest DNA degradation potential and anticancer effect among the tested complexes by leading apoptosis. Wound healing and invasion analysis results also supported the higher anticancer activity of those complexes.
Across the globe, today, cancer accounts for many fatalities, thus calling for better and updated antineoplastic agents within biomedicine and health sciences. In this regard, inorganic chemistry for pharmaceutic purposes is essential in creating drugs based in metal to fight cancer as such medicine has been shown to be potentially effective to fight cancer in humans. In light of this background, this research focuses on synthesis and anticancer activity of (2,3-di-pyridin-2-yl-quinoxaline), (2,3-di-thenyl-2-yl-quinoxaline), (2,3,2',3'-tetra-pyridin-2-yl-[6,6']biquinoxaline) and (2,3,2',3'-tetra-thenyl-2-yl-[6,6']biquinoxaline) containing copper(II) and platinum(II) compounds as prodrug candidates. The binding interaction of these compounds with calf thymus DNA (CT-DNA) and human serum albumin (HSA) of the complexes were assessed with UV titration, thermal decomposition, viscometric, and fluorometric measurements. The nature of the binding of the complexes on DNA were revealed as electrostatic interaction between the cationic metal complex ions and the negative phosphate groups of CT-DNA upon removal of one or two labile chloride ion(s), except Pt(tpbq)Cl2, Pt(ttbq)Cl2, and Cu(tpbq)Cl2; van der Waals and hydrogen bonds interaction were proposed for these complexes. In addition, our complexes induced a surface contact through the hygroscopic region of serum albumin. Antitumor activity of the complexes against human glioblastoma A172, LN229, and U87 cell lines and human lung A549, human breast MDA-231, human cervix HeLa, and human prostate PC-3 cell lines were investigated by examining cell viability (MTT), oxidative stress, apoptosis-TUNEL, in vitro migration an invasion, in vitro-Comet DNA demage, and plasmid DNA interaction assays. The U87 and HeLa cells were investigated as the cancer cells most sensitive to our complexes. The exerted cytotoxic effect of complexes was attributed to the formation of the reactive oxygen species in vitro. It is clearly demonstrated that Cu(dtq)2Cl2, Cu(ttbq)Cl2, Pt(ttbq)Cl2 and Pt(tpbq)Cl2 have the highest DNA degradation potential and anticancer effect among the tested complexes by leading apoptosis. Wound healing and invasion analysis results also supported the higher anticancer activity of those complexes.
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Keywords
Kimya, Apoptozis, Bağlama, Chemistry, Kinoksalin, Apoptosis, Binding, Kırılma, Quinoxaline, Fracture, Serbest radikaller, Free radicals
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216