KLORO[1-(2-METİL-2-PROPENİL)-3-(2-KLOROBENZİL) BENZİMİDAZOL-2-İLİDEN] Ag(I) BİLEŞİĞİNİN SH-SY5Y NÖROBLASTOM HÜCRELERİNDEKİ ANTİPROLİFERATİF AKTİVİTESİNİN ARAŞTIRILMASI

Yıl 2020, Cilt: 3 Sayı: 2, 73 - 83, 31.12.2020

Batuhan Yıldız , Serap Şahin Bölükbaşı , Neslihan Şahin

Öz

Bu çalışmada klor içeren benzimidazol-temelli N-heterosiklik karben (NHC) ligandı (1) ve ligandın gümüş-(I) kompleksinin (2) antiproliferatif aktiviteleri araştırılmıştır. Hem ligand (1) hem de kompleksin (2), SH-SY5Y nöroblastom hücrelerine ve WI-38 insan sağlıklı fibroblast hücrelerindeki antiproliferatif aktiviteleri 24 saat, 48 saat ve 72 saat boyunca (3-[4,5-Dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide; Thiazolyl blue (MTT) ölçümü kullanılarak test edilmiştir. Deney sonuçlarına göre ligand (1), tüm zaman noktalarında WI-38 sağlıklı hücrelerde antiproliferatif aktivite göstermemiş ancak SH-SY5Y nöroblastom hücrelerinde konsantrasyona ve zamana bağlı antiproliferatif aktivite göstermiştir. Sonuçlarımız, kompleksin (2), hem SH-SY5Y nöroblastom hücrelerine hem de WI-38 sağlıklı hücrelerine karşı doza ve zamana bağlı bir antiproliferatif aktiviteye sahip olduğunu göstermiştir. Ayrıca kompleksin (2), SH-SY5Y nöroblastom hücreleri ve WI-38 normal hücrelerinde liganda (1) göre daha yüksek antiproliferatif aktiviteye sahip olduğu bulunmuştur. Kompleks (2), SH-SY5Y nöroblastom hücreleri için 24 ve 48 saat zaman noktalarında 4 kattan fazla seçicilik göstermiştir.

Anahtar Kelimeler

SH-SY5Y, MTT, Antiproliferatif aktivite, N-heterosiklik karben, Gümüş

Destekleyen Kurum

-

Proje Numarası

-

Teşekkür

Antiproliferatif aktivite deneyleri Sivas Cumhuriyet Üniversitesi İleri Teknoloji Araştırma ve Uygulama Merkezi (CÜTAM)’da yapılmıştır.

INVESTIGATION on THE ANTIPROLIFERATIVE ACTIVITY OF CHLORO[1-(2-METHYL-2-PROPENYL)-3-(2-CHLOROBENZYL) BENZIMIDAZOLE-2-YLIDENE Ag(I) COMPOUND on SH-SY5Y NEUROBLASTOMA CELLS

Öz

In this study, it has been investigated the antiproliferative activities of benzimidazole-based NHC ligand (1) and its silver(I) complex (2) having chloride. Both ligand (1) and complex (2) have been tested for their antiproliferative activity on SH-SY5Y neuroblastoma cells and WI-38 human healthy fibroblast cells for 24 h, 48 h and 72 h using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. According to the experimental results, ligand (1) has not shown antiproliferative activity on WI-38 healthy cells in all-time points but has shown concentration- and time-dependent antiproliferative activity on SH-SY5Y neuroblastoma cells . Our results have shown that complex (2) has a dose and time-dependent antiproliferative activity against both SH-SY5Y neuroblastoma cells and WI-38 healthy cells. It has also been found that complex (2) has more antiproliferative activity than ligand (1) on SH-SY5Y neuroblastoma cells and WI-38 healthy cells. The IC50 value of the ligand (1) towards the SH-SY5Y neuroblastoma cell line was calculated > 20, 8.90, and 4.28 µM for 24 h, 48 h, and 72 h , respectively. IC50 values of ligand (1) against WI-38 normal lung fibroblast cell lines were calculated > 20 µM for 24, 48, and 72 hours. IC50 values of the complex (2) against SH-SY5Y neuroblastoma and WI-38 normal lung fibroblast cell lines were found to be 3.80, 3.15, and 2.21 µM; and 16.9, 14.6, and 8.34 µM for 24 h, 48 h and 72 h, respectively. The selectivity index (SI) was determined from the ratio of the IC50 value obtained from normal cells and IC50 value for cancer cells. Selectivity indexes of ligand (1) and complex (2) were calculated as >1, > 2.24, and >4.67; 4.44, 4.63 and 3.77 for 24 h, 48 and 72 h, respectively. These results indicated that complex (2) has shown good selectivity (more than 4-fold) between SH-SY5Y neuroblastoma cells and normal cells for 24 h and 48 h incubation time.

Anahtar Kelimeler

SH-SY5Y, MTT, Antiproliferative activity, N-heterocyclic carben, Silver

Proje Numarası

-

Kaynakça

• 1. Achar G., Shahini C.R., Patil S.A., Małecki J. G., Pan S.H., Lan A., Chen X.R. & Budagumpi S. (2018). Sterically modulated silver(I) complexes of coumarin substituted benzimidazol-2-ylidenes: Synthesis, crystal structures and evaluation of their antimicrobial and antilung cancer potentials. Journal of Inorganic Biochemistry, 183: 43-57.
• 2. Aher S.B., Muskawar P.N., Thenmozhi K. & Bhagat P.R. (2014). Recent developments of metal N-heterocyclic carbenes as anticancer agents. European Journal of Medicinal Chemistry, 81: 408-419.
• 3. Alpan A.S., Sarıkaya G., Çoban G., Parlar S., Armagan G. & Alptüzün V. (2017). Mannich-Benzimidazole Derivatives as Antioxidant and Anticholinesterase Inhibitors: Synthesis, Biological Evaluations, and Molecular Docking Study. Arch Pharm (Weinheim), 350(7), e1600351. doi: 10.1002/ardp.201600351.
• 4. Atif M., Bhatti H.N., Haque R.A., Iqbal M.A., Ahamed Khadeer M.B. & Majid A.M.S.A. (2020). Synthesis, Structure, and Anticancer Activity of Symmetrical and Non-symmetrical Silver(I)-N-Heterocyclic Carbene Complexes. Applied Biochemistry and Biotechnology, doi: 10.1007/s12010-019-03186-9. Online ahead of print.
• 5. Bernstein M. L., Leclerc J.M., Bunin G., Brisson L., Robison L., Shuster J., Byrne T., Gregory D., Hill G. & Dougherty G. (1992). A population-based study of neuroblastoma incidence, survival, and mortality in North America. Journal of Clinical Oncology, 10: 323–329.
• 6. Betzer J.F., Nuter F., Chtchigrovsky M., Hamon F., Kellermann G., Ali S. & Teulade-Fichou M.P. (2016). Linking of Antitumor trans NHC-Pt (II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting. Bioconjugate chemistry, 27(6), 1456-1470.
• 7. Bortenschlager, M., Schütz, J., von Preysing, D., Nuyken, O., Herrmann, W.A. & Weberskirch, R. (2005). Rhodium–NHC-complexes as potent catalysts in the hydroformylation of 1-octene. Journal of Organometallic Chemistry, 690(24), 6233-6237.
• 8. Clavier H., Urbina-Blanco C.A. & Nolan S.P. (2009). Indenylidene ruthenium complex bearing a sterically demanding NHC ligand: an efficient catalyst for olefin metathesis at room temperature. Organometallics, 28(9), 2848-2854.
• 9. DuBois S.G., Kalika Y., Lukens J.N., Brodeur G.M., Seeger R.C., Atkinson J.B., Haase G.M., Black C. T., Perez C., Shimada H., Gerbing R., Stram D.O. & Matthay K.K. (1999). Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. Journal of Pediatric Hematology/Oncology, 21(3), 181-9.
• 10. Fabbrini M.G., Cirri D., Pratesi A., Ciofi L., Marzo T., Guerri A., Nistri S., Dell'Accio A., Gamberi T., Severi M., Bencini A. & Messori L. (2019). A Fluorescent Silver(I) Carbene Complex with Anticancer Properties: Synthesis, Characterization, and Biological Studies. ChemMedChem. 14(1), 182-188.
• 11. Ge B.C., Feng H.F., Cheng Y.F., Wang H.T., Xi B.M., Yang X.M., Xu J.P. & Zhou Z.Z. (2017). Design, synthesis and biological evaluation of substituted aminopyridazin-3(2H)-ones as G0/G1-phase arresting agents with apoptosis-inducing activities. European Journal of Medicinal Chemistry, 141: 440-445.
• 12. Gutierrez J.C., Fischer A.C., Sola J.E., Perez E.A. & Koniaris L.G. (2007). Markedly improving survival of neuroblastoma: a 30-year analysis of 1,646 patients. Pediatric Surgery International, 23: 637–646.
• 13. Gürbüz N., Karaca E.Ö., Özdemir İ. & Cetinkaya B. (2015). Cross coupling reactions catalyzed by (NHC) Pd (II) complexes. Turkish Journal of Chemistry, 39(6), 1115-1157.
• 14. Haque R.A., Choo S.Y., Budagumpi S., Iqbal M.A. & Al-Ashraf Abdullah A. (2015). Silver(I) complexes of mono- and bidentate N-heterocyclic carbene ligands: synthesis, crystal structures, and in vitro antibacterial and anticancer studies. European Journal of Medicinal Chemistry, 90: 82-92.
• 15. Hu J., Guo Y., Zhao, J & Zhang J. (2017). In vitro antitumor activity of novel benzimidazole-based Cu(II) complexes. Bioorganic & Medicinal Chemistry, 25: 5733–5742.
• 16. Jakobsen V., Viganor L., Blanco-Fernández A., Howe O., Devereux M., McKenzie C.J. & McKee V. (2018). Tetrameric and polymeric silver complexes of the omeprazole scaffold; synthesis, structure, in vitro and in vivo antimicrobial activities and DNA interaction. Journal of Inorganic Biochemistry, 186: 317-328.
• 17. Kalinowska-Lis U., Felczak A., Chęcińska L., Szabłowska-Gadomska I., Patyna E., Małecki M., Lisowska K. & Ochocki J. (2016). Antibacterial Activity and Cytotoxicity of Silver(I) Complexes of Pyridine and (Benz)Imidazole Derivatives. X-ray Crystal Structure of [Ag(2,6-di(CH2OH)py)2]NO3. Molecules, 21(2), 87.
• 18. Kankala S., Thota N., Björkling F., Taylor M.K., Vadde R. & Balusu R. (2019). Silver carbene complexes: An emerging class of anticancer agents. Drug Development Research, 80(2), 188–199.
• 19. Kim S. & Chung D.H. (2006). Pediatric solid malignancies: neuroblastoma and Wilms’ tumor. Surgical Clinics of North America, 86: 469–487. xi.
• 20. Kumar A., Banerjee S., Roy P., Sondhi S.M. & Sharma A. (2018). Solvent-free synthesis and anticancer activity evaluation of benzimidazole and perimidine derivatives. Molecular Diversity, 22(1), 113-127.
• 21. Matthay K.K., Maris J.M., Schleiermacher G., Nakagawara A., Mackall C.L., Diller L. & Weiss W.A. (2016). Neuroblastoma. Nature Reviews Disease Primers, 2: 16078.
• 22. Mundy W.R., Radio N.M. & Freudenrich T.M., (2010). Neuronal models for evaluation of proliferation in vitro using high content screening. Toxicology. 270(2-3), 121-130.
• 23. Nakagawara A., Li Y., Izumi H., Muramori K., Inada H. & Nishi M. (2018). Neuroblastoma. Japanese Journal of Clinical Oncology, 48(3), 214-241.
• 24. Rao Y.J., Sowjanya T., Thirupathi G., Murthy N.Y.S. & Kotapalli S.S. (2018). Synthesis and biological evaluation of novel flavone/triazole/benzimidazole hybrids and flavone/isoxazole-annulated heterocycles as antiproliferative and antimycobacterial agents. Molecular Diversity, 22(4), 803-814.
• 25. Shi Y., Jiang K., Zheng R., Fu J., Yan L., Gu Q., Zhang Y., & Lin F. (2019). Design, Microwave-Assisted Synthesis and in Vitro Antibacterial and Antifungal Activity of 2,5-Disubstituted Benzimidazole. Chemistry & Biodiversity 16(3), e1800510. doi: 10.1002/cbdv.201800510.
• 26. Skehan P., Storeng R., Scudiero D., Monks A., McMahon J., Vistica D., Warren J.T., Bokesch H., Kenney S. & Boyd, M.R. (1990). New colorimetric cytotoxicity assay for anticancer-drug screening. Journal of the National Cancer Institute, 82(13), 1107-1112.
• 27. Şahin N., Şahin-Bölükbaşı S. & Marsan H. (2019). Synthesis and antitumor activity of new silver(I)-N-heterocyclic carbene complexes. Journal of Coordination Chemistry, 72(22-24), 3602-3613.
• 28. Şahin N., Demir S. & Özdemir İ. (2015). Transfer hydrogenation of ketones in the presence of half sandwich ruthenium (II) complexes bearing imidazoline and benzimidazole ligand. ARKIVOC, ii, 20-33.
• 29. Yu B., Qi P.P., Shi X.J., Huang R., Guo H., Zheng Y.C., Yu D.Q. & Liu, H.M. (2016). Efficient synthesis of new antiproliferative steroidal hybrids using the molecular hybridization approach. European Journal of Medicinal Chemistry, 117: 241-255.