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    Öğe
    Investigation of Some 3H-quinazolin-4-one derivatives in vitro antimicrobial effect and cytotoxicity on human gingival fibroblasts
    (Taylor & Francis Ltd, 2019) Demirel, Ural Ufuk; Yılmaz, Aydan; Türkdağı, Hatice; Öztürk, Bahadır; Arslan, Uğur
    The aim of this study is to synthesize and investigate antimicrobial and cytotoxic activity of 3 H-quinazolinone (1), and its derivatives, which are 3-(4-hydroxyphenyl)-3,4-dihydroquinazolin-4-one (2), 3-(3-hydroxyphenyl)-3,4-dihydroquinazolin-4-one (3), 3-(pyridin-3-ylmethy)-3,4-dihydroquinazolin-4-one (4) and derivatives of 2-methyl-3H-quinazolinone, which are 2-methyl-3-phenyl-3,4-dihydroquinazolin-4-one (6), 2-methyl-3(4-hydroxyphenyl)-3,4- dihydroquinazolin-4-one (7), 2-methyl-3(4-nitrophenyl)-3,4-dihydroquinazolin-4-one (8), compounds. Compounds 2 and 3 were synthesized newly. All compounds were characterized via infrared, H-1-NMR, C-13-NMR, elemental and mass spectral analysis. The compounds were screened for their antimicrobial activity in vitro against E. faecalis ATCC 29212, P. aeruginosa ATCC 27853, S. aureus ATCC 29213, E. Coli ATCC 25922 bacteria and compared with commercial antibiotics (Ampicillin and Gentamicin). The determination of the antimicrobial activity was done by using the broth microdilution methods. The antimicrobial test results indicated that the compounds (1, 4, 6, and 8) have MIC values against P. aeruginosa ATCC 27853 lower than ampicillin. But clear cytotoxic effects on proliferation of the gingival fibroblasts applications were observed in 1, 4, 6, and 8 when compared to the control group.
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    Öğe
    Kanser tedavisinde kullanılabilecek yeni bileşiklerin tasarımı, sentezi ve biyolojik etkinliklerinin araştırılması
    (Altınbaş Üniversitesi, Lisansüstü Eğitim Enstitüsü, 2021) Demirel, Ural Ufuk; Tanol, Mehmet; Ölgen, Süreyya
    Birçok kimyasal yapı arasında, kansere karşı yeni terapötik ajanlar geliştirmek için isatin türevleri yoğun bir şekilde kullanılmaktadır. İndol ya da isatin türevi (sunitinib, semaxanib ve nintedanib), bileşikler bazı kanser türlerinin tedavisi için tirozin kinaz inhibitörleri olarak halihazırda kullanılmaktadır. Sorafenib nilotinib ve ponatinib gibi amid veya üre grupları bulunduran, sunitinib gibi Schiff bazı grubu bulunduran ilaçlar kinaz inhibitörü antikanser ajanlar olarak kanser tedavisinde rol almaktadırlar. Bu tez çalışması kapsamında, isatin halkasının üçüncü konumundan elde edilen Schiff bazlarının sorafenibin yapısından esinlenerek üre, ve üre fonksiyonel grubunun biyoizosteri olan sülfonamid grubu bulunduran türevlerinin tasarlanması, sentezlenmesi, antikanser özelliklerinin HepG2, PC-3, A549, SH-SY5Y hücre hatlarına karşı test edilmesi, kimyasal yapı ile reseptöre baglanma özellikleri arasındaki ilişkinin Autodock 4.2 programı kullanılarak değerlendirilmesi ve bileşiklerin ilaca benzer özellikler taşıyıp taşımadıklarının ADME tahmin verilerine göre belirlenmesi amaçlanmıştır. Sentezlenen 16 yeni sonuç bileşiğinin ve ara basamakların kimyasal yapıları ve saflıkları erime noktası tayini, IR spektroskopisi, 1H-NMR, LC-MS analizleri, sonuç bileşikleri için ek olarak 13C-NMR analizi kullanılarak kanıtlanmıştır. Sentezlenen bileşikler arasında sonuçlar, 7a, 7b, 7c, 7d, 7h, 8a ve 8f bileşiklerinin sırasıyla, 31.97, 42.13, 31.50, 47.98, 32.59, 43.44 ve 37.81 µM IC50 değerleri ile HepG2 hücrelerine karşı hücresel proliferasyon aktivitesinin inhibisyonuna ve sağlıklı NIH/3T3 hücrelerinde zayıf sitotoksik etkiye sahip oldukları bulundu. Moleküler Docking çalışmaları, en aktif bileşik olan 7c'nin, diğer aktif bileşiklere kıyasla NS5B polimerazın reseptör bağlanma bölgesi ile etkili bağlanma özellikleri gösterdikleri ve ADME tahmin çalışmalarına göre sentezlenen tüm bileşiklerin ilaça benzer özelliklere sahip olduğu saptandı. İn vitro deneyler ve in silico çalışmalar, isatin Schiff bazlarının yeni üre ve sülfonamid türevlerinin, referans bileşik olan doksorubisin ile karşılaştırılabilecek düzeyde aktiviteye sahip olduklarını göstermiştir. Bu tip bileşiklerin hepatosellüler karsinomaya neden olan HCV-NS5B'ye karşı aktif olabileceği ve bu bileşiklere benzer tasarlanacak bileşiklerde daha etkin moleküller bulma olasılığı olduğu sonucuna varılmıştır.
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    Öğe
    Synthesis and anticancer activity of novel indole derivatives as dual EGFR/SRC kinase inhibitors
    (2023) Ölgen, Süreyya; Biltekin Kaleli, Sevde Nur; Taktak Karaca, Banu; Demirel, Ural Ufuk; Karataş Bristow, Hacer
    Background: Recent studies showed that the cooperation between c-SRC and EGFR is responsible for more aggressive phenotype in diverse tumors, including glioblastomas and carcinomas of the colon, breast, and lung. Studies show that combination of SRC and EGFR inhibitors can induce apoptosis and delay the acquired resistance to chemotherapy. Therefore, such combination may lead to a new therapeutic strategy for the treatment of EGFR-mutant lung cancer. Osimertinib was developed as a third-generation EGFR-TKI to combat the toxicity of EGFR mutant inhibitors. Due to the resistance and adverse reaction of osimertinib and other kinase inhibitors, 12 novel compounds structurally similar to osimertinib were designed and synthesized. Background: Recent studies showed that the cooperation between c-SRC and EGFR is responsible for more aggressive phenotype in diverse tumors, including glioblastomas and carcinomas of the colon, breast, and lung. Studies show that combination of SRC and EGFR inhibitors can induce apoptosis and delay the acquired resistance to chemotherapy. Therefore, such combination may lead to a new therapeutic strategy for the treatment of EGFR-mutant lung cancer. Osimertinib was developed as a third-generation EGFR-TKI to combat the toxicity of EGFR mutant inhibitors. Due to the resistance and adverse reaction of osimertinib and other kinase inhibitors, 12 novel compounds structurally similar to osimertinib were designed and synthesized. Methods: Compounds were synthesized by developing novel original synthesis methods and receptor interactions were evaluated through a molecular docking study. To evaluate their inhibitory activities against EGFR and SRC kinase, in vitro enzyme assays were used. Anticancer potencies were determined using lung, breast, prostate (A549, MCF6, PC3) cancer cell lines. Compounds were also tested against normal (HEK293) cell line to evaluate their cyctotoxic effects. Results: Although, none of compounds showed stronger inhibition compared to osimertinib in the EGFR enzyme inhibition studies, compound 16 showed the highest efficacy with an IC50 of 1.026 μM. It also presented potent activity against SRC kinase with an IC50 of 0.002 μM. Among the tested compounds, the urea containing derivatives 6-11 exhibited a strong inhibition profile (80.12-89.68%) against SRC kinase in comparison to the reference compound dasatinib (93.26%). Most of the compounds caused more than 50% of cell death in breast, lung and prostate cancer cell lines and weak toxicity for normal cells in comparison to reference compounds osimertinib, dasatinib and cisplatin. Compound 16 showed strong cytotoxicity on lung and prostate cancer cells. Treatment of prostate cancer cell lines with the most active compound, 16, significantly increased the caspase-3 (8-fold), caspase-8 (6-fold) and Bax (5.7-fold) levels and decreased the Bcl-2 level (2.3-fold) compared to the control group. These findings revealed that the compound 16 strongly induces apoptosis in the prostate cancer cell lines. Conclusion: Overall kinase inhibition, cytotoxicity and apoptosis assays presented that compound 16 has dual inhibitory activity against SRC and EGFR kinases while maintaining low toxicity against normal cells. Other compounds also showed considerable activity profiles in kinase and cell culture assays.
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    Öğe
    Synthesis of novel urea and sulfonamide derivatives of isatin schiff bases as potential anti-cancer agents
    (Bentham Science Publishers, 2022) Demirel, Ural Ufuk; Ölgen, Süreyya; Karaman, Ecem Fatma; Tanol, Mehmet; Özden, Sibel; Göker, Hakan
    Background: Among the many types of chemical scaffolds, isatin derivatives, including their Schiff bases, have been extensively studied to find novel therapeutic agents against cancer. Amide or urea groups containing derivatives were also discovered to be tyrosine kinase inhibitors. Objective: This study aims to find potent compounds by designing 16 novel urea and sulfonamide derivatives of isatin Schiff bases. Methods: Compounds were tested against PC-3, HepG2, SH-SY5Y, A549 cancerous, and NIH/3T3 non-cancerous cell lines using cell culture assay. Results: Among the tested compounds 7a, 7b, 7c, 7d, 7h, 8a, and 8f presented potential inhibitions against cellular proliferation activities of HepG2 cells with average IC50 values of 31.97, 42.13, 31.50, 47.98, 32.59, 43.44, and 37.81 µM, respectively. They showed better inhibition potencies than the reference compound doxorubicin, and its value was measured as 51.15 μM in the same culture assay. The cytotoxic activities of the compounds in other cell lines were found to be less potent compared to doxoru-bicin. Conclusion: In vitro experiments demonstrated that designed compounds have the first evidence that they might be active against hepatocellular carcinoma. According to ADME prediction results, all compounds presented drug-like and good metabolic properties.