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  • Küçük Resim
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    BSA/DNA binding behavior and the photophysicochemical properties of novel water soluble zinc (II) phthalocyanines directly substituted with piperazine groups
    (2021/6) Khezami, Khaoula; Harmandar, Kevser; Bağda, Esra; Bağda, Efkan; Şahin, Gamze; Karakodak, Nurşen; Durmuş, Mahmut
    In the current research, two novel zinc(II) phthalocyanines (ZnPcs) (1 and 2) directly connecting with 4-(4-methylpiperazin-1-yl)phenyl groups have been synthesized through the Suzuki–Miyaura coupling reaction. These ZnPcs 1 and 2 were converted to their water-soluble derivatives (1Q and 2Q) by quaternization. The photochemical and photophysical properties were determined in DMSO for the non-ionic zinc(II) phthalocyanines (1 and 2) and in both DMSO and aqueous solutions for the quaternized cationic derivatives (1Q and 2Q) to establish their photosensitizer capabilities in photodynamic therapy (PDT). The spectrofluorometric and spectrophotometric techniques were employed for the determination of interaction between water-soluble ZnPcs (1Q and 2Q) and BSA or ct-DNA. The binding constants of these compounds to BSA were found in the order of 108 M−1. The binding constant of the ct-DNA interaction with 2Q (1.09 × 105 M−1) was found higher than 1Q (6.87 × 104 M−1). The thermodynamic constants were determined for both 1Q and 2Q. The endothermic and spontaneous nature of interaction was observed with ct-DNA. Besides, the thermal denaturation and viscosity studies proved the non-intercalative mode of binding for both compounds to ct-DNA.
  • Küçük Resim
    Öğe
    BSA/DNA binding behavior and the photophysicochemical properties of novel water soluble zinc (II) phthalocyanines directly substituted with piperazine groups
    (Springer, 2021/05/04) Bağda, Efkan; Harmandar, Kevser; Bağda, Esra; Şahin, Gamze; Karakodak, Nurşen; Durmuş, Mahmut; Khezami, Khaoula
    In the current research, two novel zinc(II) phthalocyanines (ZnPcs) (1 and 2) directly connecting with 4-(4-methylpiperazin-1-yl)phenyl groups have been synthesized through the Suzuki–Miyaura coupling reaction. These ZnPcs 1 and 2 were converted to their water-soluble derivatives (1Q and 2Q) by quaternization. The photochemical and photophysical properties were determined in DMSO for the non-ionic zinc(II) phthalocyanines (1 and 2) and in both DMSO and aqueous solutions for the quaternized cationic derivatives (1Q and 2Q) to establish their photosensitizer capabilities in photodynamic therapy (PDT). The spectrofluorometric and spectrophotometric techniques were employed for the determination of interaction between water-soluble ZnPcs (1Q and 2Q) and BSA or ct-DNA. The binding constants of these compounds to BSA were found in the order of 108 M−1. The binding constant of the ct-DNA interaction with 2Q (1.09 × 105 M−1) was found higher than 1Q (6.87 × 104 M−1). The thermodynamic constants were determined for both 1Q and 2Q. The endothermic and spontaneous nature of interaction was observed with ct-DNA. Besides, the thermal denaturation and viscosity studies proved the non-intercalative mode of binding for both compounds to ct-DNA.
  • Küçük Resim Yok
    Öğe
    Development of quantum dot-phthalocyanine integrated G-quadruplex /double-stranded DNA biosensor
    (Academic Press Inc., 2022) Topcu, Ayşe; Bağda, Esra; Oymak, Tülay; Durmuş, Mahmut
    In the present study, the phthalocyanine (Pc) integrated mercaptopropionic acid capped quantum dot (mpa@QD) biosensor has been developed for the quantitative determination of G-quadruplex and double-stranded DNA. The working principle of the developed biosensor platform is based on the quenching of the emission signal of the mpa@QD in the presence of Pc (closed position) and the recovery of the fluorescence signal in the presence of DNA (open position). The parameters affecting biosensor performance, such as Pc type and concentration, were optimized. Since the developed biosensor aimed to determine G-quadruplex and double-stranded DNA in biological samples, the effect of common ions (such as Na+, Mg2+) and serum albumin found in many biological matrices on the biosensor performance were examined. The effect of common ions on biosensor signal was negligible, except Zn2+. The analytical properties of the biosensor, such as linear range, calibration sensitivity, relative standard deviation %, the limit of detection, and quantification, were determined. The limit of detection and quantification values were found 0.055 ?M and 0.18 ?M for AS1411, 0.061 ?M and 0.20 ?M for Tel21, 0.038 ?M and 0.13 ?M for Tel45 and 0.091 ?M and 0.30 ?M for ctDNA. Several different synthetic samples were prepared. The spiked synthetic samples such as mammalian cell medium were used to evaluate the analytical performance of Pc-mpa@QD. All synthetic samples were prepared with polyethylene glycol, which resembles biological samples' crowded environment. © 2022 Elsevier Inc.
  • Küçük Resim
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    Interaction of water soluble cationic gallium (III) phthalocyanines with different G-quadruplex DNAs
    (Elsevier, 2021/11/1) Bağda, Efkan; Bağda, Esra; Durmuş, Mahmut; Yılmaz, Hasan Emre
    Small molecule-G-quadruplex DNA interaction has been gained considerable interest due to existence of G-quadruplex structures in telomeres and promotor regions of proto-oncogenes. In the present study, the interaction of 2(3), 9(10), 16(17), 23(24)-tetrakis-[(N-methyl-3-pyridyloxy)phthalocyaninato]chloro gallium (III) sulphate (TGaPc) and 2, 3, 9, 10, 16, 17, 23, 24-octakis-[(N-methyl-3-pyridyloxy) phthalocyaninato]chloro gallium (III) sulphate (OGaPc) with different DNA forms (ctDNA and G-quadruplex DNAs) was investigated. The interactions of compounds with DNA was extensively investigated by different methods, such as capillary gel electrophoresis (CGE) integrated with a high sensitivity LED-induced fluorescence detector, UV–Vis and circular dichroism spectroscopy, competitive dialysis experiments. UV–Vis. titrations and CGE studies showed that the two phthalocyanine compounds interacted with the G-quadruplex and ctDNA, but the binding affinity of TGaPc was high for AS1411. Dialysis experiments also supported the higher affinity of TGaPc to AS1411. CD studies showed that both TGaPc and OGaPc caused destabilization of Tel21 structure even at low concentrations. This was more or less observed in other G-quadruplex DNAs other than AS1411. The structure of AS1411 remained intact at binding stoichiometric ratios. The viscosimetric studies and gel electrophoresis studies have been used to explore the interaction of TGaPc and OGaPc with ctDNA. The viscosity experiments along with gel electrophoresis confirmed the intercalation binding for ctDNA with OGaPc and groove binding for TGaPc. All results show that these molecules interact with different DNA types at different strengths and different mechanisms and the binding affinity of TGaPc was high for AS1411. Therefore, these compounds have the potential for cancer treatment.
  • Küçük Resim
    Öğe
    Interaction of water soluble cationic gallium (III) phthalocyanines with different G-quadruplex DNAs
    (Elsevier, 1 November 2021) Yılmaz, Hasan Emre; Bağda, Efkan; Bağda, Esra; Durmuş, Mahmut
    Small molecule-G-quadruplex DNA interaction has been gained considerable interest due to existence of G-quadruplex structures in telomeres and promotor regions of proto-oncogenes. In the present study, the interaction of 2(3), 9(10), 16(17), 23(24)-tetrakis-[(N-methyl-3-pyridyloxy)phthalocyaninato]chloro gallium (III) sulphate (TGaPc) and 2, 3, 9, 10, 16, 17, 23, 24-octakis-[(N-methyl-3-pyridyloxy) phthalocyaninato]chloro gallium (III) sulphate (OGaPc) with different DNA forms (ctDNA and G-quadruplex DNAs) was investigated. The interactions of compounds with DNA was extensively investigated by different methods, such as capillary gel electrophoresis (CGE) integrated with a high sensitivity LED-induced fluorescence detector, UV–Vis and circular dichroism spectroscopy, competitive dialysis experiments. UV–Vis. titrations and CGE studies showed that the two phthalocyanine compounds interacted with the G-quadruplex and ctDNA, but the binding affinity of TGaPc was high for AS1411. Dialysis experiments also supported the higher affinity of TGaPc to AS1411. CD studies showed that both TGaPc and OGaPc caused destabilization of Tel21 structure even at low concentrations. This was more or less observed in other G-quadruplex DNAs other than AS1411. The structure of AS1411 remained intact at binding stoichiometric ratios. The viscosimetric studies and gel electrophoresis studies have been used to explore the interaction of TGaPc and OGaPc with ctDNA. The viscosity experiments along with gel electrophoresis confirmed the intercalation binding for ctDNA with OGaPc and groove binding for TGaPc. All results show that these molecules interact with different DNA types at different strengths and different mechanisms and the binding affinity of TGaPc was high for AS1411. Therefore, these compounds have the potential for cancer treatment.
  • Küçük Resim
    Öğe
    Investigation of Binding behaviour of a water-soluble gallium (III) phthalocyanine with double-stranded and G-quadruplex DNA via experimental and computational methods
    (Elsevier, 2021/15/09) Bağda, Efkan; Bağda, Esra; Koçak, Abdulkadir; Durmuş, Mahmut
    DNA is an important target for the development of chemotherapeutic drug design due to increased and uncontrolled cell proliferation of cancer cells. In the present study, the affinity of water-soluble gallium(III) phthalocyanine chloride (GaPc) non-peripherally substituted with 2-mercapto-N-methylpyridinium groups to different types of DNA (double-stranded ctDNA and G-quadruplex DNA) was investigated. The interaction mechanisms were evaluated by UV-Vis, fluorescence and circular dichroism spectroscopic techniques, competitive dialysis assay, and capillary gel electrophoresis (CGE) system integrated with a high sensitivity LED-induced fluorescence (LIF) detector. Binding mode studies were carried out by molecular docking and molecular dynamic simulations. The experimental binding constants were determined as 1.9 × 106 M−1, 1.1 × 106 M−1, 8.5 × 105 M−1, 2.9 × 104 M−1 for c-MYC, AS1411, Tel21, and ctDNA, respectively. Competitive binding assay confirmed the higher affinity towards G-quadruplex structure rather than ctDNA. The GaPc-G-quadruplex DNA conjugates showed higher Kb constants and a strong absorption band closer to NIR window which is a desired feature for the photodynamic therapy applications. Besides, experimental data show that the formation of GaPc-G-quadruplex DNA conjugates reduced the aggregation of GaPc. Reduction of aggregation of phthalocyanine is important. Because aggregation decreases the photoactivity of most photosensitizers. The experimental results suggested that both intercalative and non‑intercalative binding contributions occurred in the case of double-stranded ctDNA. Confirming experiments, molecular docking studies showed that the GaPc can bind from two different major groove regions in double-stranded DNA while only one binding mode was observed in the G-quadruplex DNA. Both experimental and computational studies suggested that the conformational change and unfolding mechanism in G-quadruplex DNA structure were determined upon interaction with GaPc.
  • Küçük Resim Yok
    Öğe
    Nükleolin Hedefli G-Quadrupleks Taşıyıcı Sisteme Dayalı Akıllı Kemoterapötik Ajan Geliştirilmesi ve Fotodinamik Terapide Uygulamaları
    (2021) Bağda, Esra; Gürsan, Kadriye Arzum Erdem; Durmuş, Mahmut; Altun, Ahmet; Bağda, Efkan; Şahin, Gamze; Aydın, Fadime
    Dünya sağlık örgütü verilerine göre 2020 yılında 2,2 milyondan fazla vaka sayısı ile meme kanseri en yaygın görülen kanser türlerindendir. Yaklaşık her 12 kadından biri hayatları boyunca meme kanserine yakalanmaktadır ve kadınlarda kanser kaynaklı ölümlerin başında meme kanseri gelmektedir. Meme kanseri ölüm vakaları daha çok orta ve düşük düzeyli ekonomiye sahip ülkelerde görülmektedir. Ekonomik, etkin ve ulaşılabilir meme kanseri tedavisi mortalite verilerinde iyileşmeye neden olacaktır. Kanserleşme hücre proliferasyonundaki değişikliklerle birlikte hücre, yüzeyinde bulunan kompleks yapılarda meydana gelen fiziksel ve kimyasal değişimler olarak tanımlanır. Kanserleşme ile birlikte hücre yüzey belirteçlerinin farklılaşması, bazı proteinlerin ekspresyonundaki değişimeler kanser yüzey belirteçlerini ilaç hedefleri olarak kullanımını sağlamaktadır. Nükleolin meme kanseri gibi bazı önemli kanser türlerinde yüzey ekspresyonu artan proteinlerden bir tanesidir. Hücre yüzey biyobelirteçlerini hedefleyen önemli yöntemlerden biri nükleik asit temelli aptamerlerdir. Aptamerler kolay ve ucuz kimyasal yöntemlerle sentezlenebilmeleri, sentez tekrarlanırlıklarının yüksek olması, ticari olarak fazla miktarda üretilebilmeleri, kolaylıkla modifiye edilebilmeleri, kararlılıkları, toksik olmamaları, özellikle antidotlar için agnostik (yarışmacı) aptamerlerin bulunması, dokulara hızlı penetrasyonları ve düşük immünojenizitelerinden dolayı antikorlara göre daha avantajlı terapötik ajanlardır. Ftalosiyaninler, singlet oksijen kuantum verimleri yüksek, konjüge ? sistemlerine sahip, biyomoleküller ile etkileşime uygun düzlemsel bileşiklerdir. Bu bileşikler uygun ışıma ile uyarıldıklarında fototoksik singlet oksijen oluşturabilmelerinden dolayı fotodinamik terapi için oldukça kullanışlı fotoduyarlı ajanlardır. Fotodinamik terapi (FDT) herhangi bir ilaç direncinin gelişimine neden olmaması, yan etkilerinin az olması, dokuya hedeflenebilir olması, ucuz ve kolay uygulanabilmesi ve gerçek zamanlı dozaj ayarlanmasına olanak sağlaması gibi birçok avantaja sahip terapi yöntemidir. Bu tedavinin etkinliği tümöre fotoduyarlaştırıcı ajanın etkin birikimi ile doğrudan alakalıdır. Proje kapsamında, Fs-AS1411 konjugantları geliştirilerek meme kanseri FDT sinde kullanabilirlikleri araştırılmıştır. Çalışma için suda çözünen, merkezinde In ve Ga atomları bulunduran periferal-tetra, non-periferal-tetra ve periferal-okta (4-merkaptopiridin) sübstitüe Fs molekülleri sentezlenerek karakterize edilmiştir. Elde edilen Fs molekülleri, nükleonine kuvvetli affinite gösteren AS1411 G-quadrupleks aptameri ile etkileştirilerek konjugantlar oluşturulmuştur. Fs-AS1411 konjugantlarının konformasyonal değişimi, stabilitesi gibi bir çok özelliği belirlenmiştir. Ayrıca, Fs-AS1411 etkileşimi kolay uygulanabilir, maliyeti düşük, hızlı, duyarlı ve seçimli analizi mümkün kılan elektrokimyasal yöntemlerle de tayin edildi. Geliştirilen konjugantların fotositotoksik etkisi meme kanseri (MCF-7) ve doxorubicin dirençli (MCF-7R) meme kanseri ile meme bezi (MCF-10A) hücre hatları kullanılarak araştırıldı. Ayrıca Fs-AS1411 konjugant sisteminin seçiciliği ve terapötik kapasitesi diğer bir kemoterapötik ajan olan doxorubicin ile kıyaslanmıştır.