TY  - JOUR
T1  - Novel thiazole/ethyl thiazole carboxylate-acetamide derivatives and their cytotoxic effect evaluation
TT  - Yeni tiyazol/etil tiyazol karboksilat-asetamid türevleri ve bunların sitotoksik etkisinin değerlendirilmesi
AU  - Evren, Asaf Evrim
AU  - Dawbaa, Sam
AU  - Nuha, Demokrat
AU  - Kaya, Aybüke Züleyha
AU  - Canturk, Zerrin
AU  - Yurttaş, Leyla
PY  - 2024
DA  - June
Y2  - 2024
DO  - 10.30607/kvj.1430771
JF  - Kocatepe Veterinary Journal
JO  - kvj
PB  - Afyon Kocatepe University
WT  - DergiPark
SN  - 1308-1594
SP  - 104
EP  - 116
VL  - 17
IS  - 2
LA  - en
AB  - In this study, the main goal is to determine the anticancer compound(s) that can be used against A549 non-small lung epithelial carcinoma, Caco-2 colon carcinoma, and SHSY-5Y neuroblastoma cells with high selectivity. For this purpose, our study group synthesized two similar acetamide series: four compounds (3a–3d), including thiazole, and four compounds (3e–3h), including ethyl (4-methyl-thiazol-5-yl)carboxylate. The structural analyses of eight compounds were identified by HRMS, 1H-NMR, and 13C-NMR. After approving the purity, their anticancer profiles were evaluated against above cancer cells, and the cytotoxicity effect was also tested against NIH/3T3 fibroblast cells. Meanwhile, ADME and DFT calculations indicated that compounds have good ADME profiles and chemical stability.  Among the targeted compounds, compound 3g exhibits greater stability. In chemical systems, stability is important because it represents the energy balance within a molecule. The results showed that compounds have significant impact on SHSY-5Y cells with higher selectivity than other cells. The combination of ester groups on thiazole and thiazoline (compound 3g) was found to be significantly more effective than doxorubicin and highly selective on SHSY-5Y cells than healthy cells. Besides that, combination of thiazole and triazole (3d and 3h) decreased antiproliferative activity in three cancer cells while increasing cytotoxicity in healthy cells. This study suggests that future perspectives in studies regarding the treatments of neuroblastoma and its related diseases of ethyl 2-acetamido-4-methylthiazole-5-carboxylate and thiazoline combination are encouraging.
KW  - Thiazole
KW  - Ethyl carboxylate
KW  - DFT
KW  - Anticancer activity
KW  - SHSY-5Y
N2  - Bu çalışmada A549 küçük olmayan akciğer epitelyal karsinomu, Caco-2 kolon karsinomu ve SHSY-5Y nöroblastoma hücrelerine karşı kullanılabilecek yüksek seçiciliğe sahip antikanser bileşik(ler)in belirlenmesi temel amaçtır. Bu amaçla çalışma grubumuz tiyazol içeren dört bileşik (3a-3d) ve etil (4-metil-tiyazol-5-il)karboksilat içeren dört bileşik (3e-3h) şeklinde benzer iki asetamit serisi sentezledi. Sekiz bileşiğin yapısal analizleri HRMS, 1H-NMR ve 13C-NMR ile tanımlandı. Saflık onaylandıktan sonra yukarıdaki kanser hücrelerine karşı antikanser profilleri değerlendirildi ve ayrıca NIH/3T3 fibroblast hücrelerine karşı sitotoksisite etkisi test edildi. Bu arada ADME ve DFT hesaplamaları bileşiklerin iyi ADME profillerine ve kimyasal stabiliteye sahip olduğu belirlendi. Hedeflenen bileşikler arasında bileşik 3g daha fazla stabilite sergilemektedir. Kimyasal sistemlerde stabilite önemlidir çünkü bir molekül içindeki enerji dengesini temsil eder. Sonuçlar, bileşiklerin SHSY-5Y hücreleri üzerinde diğer hücrelere göre daha seçici bir etkiye sahip olduğunu gösterdi. Tiyazol üzerindeki ester grubu ile tiyazolidin (bileşik 3g) kombinasyonunun doksorubisinden anlamlı derecede etkili olduğu ve SHSY-5Y hücreleri üzerinde sağlıklı hücrelere göre oldukça seçici olduğu bulundu. Bunun yanı sıra, tiyazol-triazol kombinasyonu (3d ve 3h) üç kanser hücresinde de antiproliferatif aktiviteyi azaltırken, sağlıklı hücrede sitotoksisiteyi arttırdı. Bu çalışma ile nöroblastoma ve bununla ilişkili hastalıkların tedavisine ilişkin çalışmalarda etil 2-asetamido-4-metiltiyazol-5-karboksilat ve tiyazolin kombinasyonunun gelecekteki yaklaşımlar için ümit verici olduğunu ileri sürmektedir.
CR  - Ahmed, K., Matsuya, Y., Nemoto, H., Zaidi, S.F., Sugiyama, T., Yoshihisa, Y., Shimizu, T., Kondo, T. (2009). Mechanism of apoptosis induced by a newly synthesized derivative of macrosphelides with a thiazole side chain. Chem Biol Interact, 177 (3), 218-226. 10.1016/j.cbi.2008.10.030
CR  - Altintop, M.D., Kaplancikli, Z.A., Ciftci, G.A., Demirel, R. (2014). Synthesis and biological evaluation of thiazoline derivatives as new antimicrobial and anticancer agents. Eur. J. Med. Chem., 74, 264-277. 10.1016/j.ejmech.2013.12.060
CR  - Bhagat, D.S., Chawla, P.A., Gurnule, W.B., Shejul, S.K., Bumbrah, G.S. (2021). An Insight into Synthesis and Anticancer Potential of Thiazole and 4-thiazolidinone Containing Motifs. Current Organic Chemistry, 25 (7), 819-841. 10.2174/1385272825999210101234704
CR  - Bhat, U.G., Halasi, M., Gartel, A.L. (2009). Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS One, 4 (5), e5592. 10.1371/journal.pone.0005592
CR  - Catarzi, D., Varano, F., Vigiani, E., Lambertucci, C., Spinaci, A., Volpini, R., Colotta, V. (2022). Casein Kinase 1delta Inhibitors as Promising Therapeutic Agents for Neurodegenerative Disorders. Curr Med Chem, 29 (27), 4698-4737. 10.2174/0929867329666220301115124
CR  - Cavalier, H., Trasande, L., Porta, M. (2023). Exposures to pesticides and risk of cancer: Evaluation of recent epidemiological evidence in humans and paths forward. International Journal of Cancer, 152 (5), 879-912.
CR  - Cortes, A.J. (2019). Molecular biology of cancer: similarities between humans and animals. Revista Veterinaria y Zootecnia (On Line), 13 (2), 81-95.
CR  - Dawbaa, S., Evren, A.E., Cantürk, Z., Yurttaş, L. (2021). Synthesis of new thiazole derivatives and evaluation of their antimicrobial and cytotoxic activities. Phosphorus Sulfur Silicon Relat Elem, 196 (12), 1093-1102. 10.1080/10426507.2021.1972299
CR  - Dawbaa, S., Nuha, D., Evren, A.E., Cankiliç, M.Y., Yurttaş, L., Turan, G. (2023). New oxadiazole/triazole derivatives with antimicrobial and antioxidant properties. J Mol Struct, 1282, 135213. 10.1016/j.molstruc.2023.135213
CR  - Delaney, G., Jacob, S., Featherstone, C., Barton, M. (2005). The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer, 104 (6), 1129-1137. 10.1002/cncr.21324
CR  - Dennington, R., Keith, T., Millam, J. (2009): GaussView, version 5.
CR  - Dileep, K., Katiki, M.R., Rao, B.R., Vardhan, V.P.S.V., Sistla, R., Nanubolu, B., Murty, M.S.R. (2017). Regioselective synthesis and preliminary cytotoxic activity properties of tetrazole appendage N-substituted piperazine derivatives. Organic Communications, 10 (3), 178-189. 10.25135/acg.oc.20.17.04.018
CR  - Dora, D., Bokhari, S.M.Z., Aloss, K., Takacs, P., Desnoix, J.Z., Szklenarik, G., Hurley, P.D., Lohinai, Z. (2023). Implication of the Gut Microbiome and Microbial-Derived Metabolites in Immune-Related Adverse Events: Emergence of Novel Biomarkers for Cancer Immunotherapy. Int J Mol Sci, 24 (3)10.3390/ijms24032769
CR  - El-Gazzar, Y.I., Georgey, H.H., El-Messery, S.M., Ewida, H.A., Hassan, G.S., Raafat, M.M., Ewida, M.A., El-Subbagh, H.I. (2017). Synthesis, biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors. Bioorg Chem, 72, 282-292. 10.1016/j.bioorg.2017.04.019
CR  - Eslami, M., Memarsadeghi, O., Davarpanah, A., Arti, A., Nayernia, K., Behnam, B. (2024). Overcoming Chemotherapy Resistance in Metastatic Cancer: A Comprehensive Review. Biomedicines, 12 (1), 183. 10.3390/biomedicines12010183
CR  - Evren, A.E., Nuha, D., Dawbaa, S., Karaduman, A.B., Saglik, B.N., Yurttas, L. (2023). Novel oxadiazole-thiadiazole derivatives: synthesis, biological evaluation, and in silico studies. J Biomol Struct Dyn, 1-13. 10.1080/07391102.2023.2247087
CR  - Evren, A.E., Yurttas, L., Ekselli, B., Akalin-Ciftci, G. (2019a). Synthesis and biological evaluation of 5-methyl-4-phenyl thiazole derivatives as anticancer agents. Phosphorus Sulfur Silicon Relat Elem, 194 (8), 820-828. 10.1080/10426507.2018.1550642
CR  - Evren, A.E., Yurttaş, L., Eksellı, B., Akalın-Cıftcı, G. (2019b). Novel Tri-substituted Thiazoles Bearing Piperazine Ring: Synthesis and Evaluation of their Anticancer Activity. Lett Drug Des Discov, 16 (5), 547-555. 10.2174/1570180815666180731122118
CR  - Falzone, L., Bordonaro, R., Libra, M. (2023). SnapShot: Cancer chemotherapy. Cell, 186 (8), 1816-1816.e1811. 10.1016/j.cell.2023.02.038
CR  - Freitas, S.C., Sanderson, D., Caspani, S., Magalhaes, R., Cortes-Llanos, B., Granja, A., Reis, S., Belo, J.H., Azevedo, J., Gomez-Gaviro, M.V., Sousa, C.T. (2023). New Frontiers in Colorectal Cancer Treatment Combining Nanotechnology with Photo- and Radiotherapy. Cancers (Basel), 15 (2)10.3390/cancers15020383
CR  - Frisch, M., Trucks, G., Schlegel, H., Scuseria, G., Robb, M., Cheeseman, J., Scalmani, G., Barone, V., Mennucci, B., Petersson, G. (2009): Gaussian09, Revision A. Wallingford CT Inc., pp. 150-166.
CR  - Gallego, J., Varani, G. (2001). Targeting RNA with small-molecule drugs: therapeutic promise and chemical challenges. Acc Chem Res, 34 (10), 836-843. 10.1021/ar000118k
CR  - Hernandes, E.P., Lazarin-Bidoia, D., Bini, R.D., Nakamura, C.V., Cotica, L.F., de Oliveira Silva Lautenschlager, S. (2023). Doxorubicin-Loaded Iron Oxide Nanoparticles Induce Oxidative Stress and Cell Cycle Arrest in Breast Cancer Cells. Antioxidants (Basel), 12 (2)10.3390/antiox12020237
CR  - Hernández-Paredes, J., Glossman-Mitnik, D., Duarte-Moller, A., Flores-Holguín, N. (2009). Theoretical calculations of molecular dipole moment, polarizability, and first hyperpolarizability of glycine–sodium nitrate. Journal of Molecular Structure: THEOCHEM, 905 (1-3), 76-80. 10.1016/j.theochem.2009.03.014
CR  - Hoelder, S., Clarke, P.A., Workman, P. (2012). Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol Oncol, 6 (2), 155-176. 10.1016/j.molonc.2012.02.004
CR  - Holohan, C., Van Schaeybroeck, S., Longley, D.B., Johnston, P.G. (2013). Cancer drug resistance: an evolving paradigm. Nat Rev Cancer, 13 (10), 714-726. 10.1038/nrc3599
CR  - Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., Sarkar, S. (2014). Drug resistance in cancer: an overview. Cancers (Basel), 6 (3), 1769-1792. 10.3390/cancers6031769
CR  - Kavitha, J., Sivakrishnan, S., Srinivasan, N. (2022). Self-Medication in Today's Generation without Knowledge as Self Inflicted Harm. Archives Of Pharmacy Practice, 13 (3), 16-22. 10.51847/PXyGs4x42h
CR  - Kleinman, D.A. (1962). Nonlinear Dielectric Polarization in Optical Media. Physical Review, 126 (6), 1977-1979. 10.1103/PhysRev.126.1977
CR  - Kwon, J.H., Tanco, K., Park, J.C., Wong, A., Seo, L., Liu, D., Chisholm, G., Williams, J., Hui, D., Bruera, E. (2015). Frequency, Predictors, and Medical Record Documentation of Chemical Coping Among Advanced Cancer Patients. Oncologist, 20 (6), 692-697. 10.1634/theoncologist.2015-0012
CR  - Laiolo, J., Graikioti, D.G., Barbieri, C.L., Joray, M.B., Antoniou, A.I., Vera, D.M.A., Athanassopoulos, C.M., Carpinella, M.C. (2024). Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein. Sci Rep, 14 (1), 70. 10.1038/s41598-023-49939-9
CR  - Li, Q., Xu, N., Lin, M., Chen, Y., Li, H. (2024). Successful treatment of severe lung cancer caused by third-generation EGFR-TKI resistance due to EGFR genotype conversion with afatinib plus anlotinib. Anticancer Drugs, 35 (1), 93-96. 10.1097/CAD.0000000000001530
CR  - Markovic, A., Zivkovic, A., Atanasova, M., Doytchinova, I., Hofmann, B., George, S., Kretschmer, S., Rodl, C., Steinhilber, D., Stark, H., Smelcerovic, A. (2023). Thiazole derivatives as dual inhibitors of deoxyribonuclease I and 5-lipoxygenase: A promising scaffold for the development of neuroprotective drugs. Chem Biol Interact, 381, 110542. 10.1016/j.cbi.2023.110542
CR  - McGhee, W.R., Dempster, M., Graham-Wisener, L. (2022). The role of companion animals in advanced cancer: an interpretative phenomenological analysis. BMC palliative care, 21 (1), 160.
CR  - Nitkin, P. (2014): Being there: relationships between people with cancer and their pets: what helps and what hinders. University of British Columbia.
CR  - Nitkin, P., Buchanan, M.J. (2020). Relationships between people with cancer and their companion animals: what helps and hinders. Anthrozoös, 33 (2), 243-259.
CR  - Nuha, D., Evren, A.E., Ciyanci, Z.S., Temel, H.E., Akalin Ciftci, G., Yurttas, L. (2022). Synthesis, density functional theory calculation, molecular docking studies, and evaluation of novel 5-nitrothiophene derivatives for anticancer activity. Arch Pharm (Weinheim), 355 (9), e2200105. 10.1002/ardp.202200105
CR  - Nuha, D., Evren, A.E., Kapusiz, Ö., Gül, Ü.D., Gundogdu-Karaburun, N., Karaburun, A.Ç., Berber, H. (2023). Design, synthesis, and antimicrobial activity of novel coumarin derivatives: An in-silico and in-vitro study. J Mol Struct, 1272, 134166. 10.1016/j.molstruc.2022.134166
CR  - Ocansey, D.K.W., Qian, F., Cai, P., Ocansey, S., Amoah, S., Qian, Y., Mao, F. (2024). Current evidence and therapeutic implication of PANoptosis in cancer. Theranostics, 14 (2), 640-661. 10.7150/thno.91814
CR  - Oh, J.H., Cho, J.-Y. (2023a). Comparative oncology: overcoming human cancer through companion animal studies. Experimental & Molecular Medicine, 55 (4), 725-734.
CR  - Oh, J.H., Cho, J.Y. (2023b). Comparative oncology: overcoming human cancer through companion animal studies. Exp Mol Med, 55 (4), 725-734. 10.1038/s12276-023-00977-3
CR  - Osmaniye, D., Evren, A.E., Karaca, Ş., Özkay, Y., Kaplancıklı, Z.A. (2023). Novel thiadiazol derivatives; design, synthesis, biological activity, molecular docking and molecular dynamics. J Mol Struct, 1272, 134171. 10.1016/j.molstruc.2022.134171
CR  - Osmaniye, D., Levent, S., Sağlık, B.N., Karaduman, A.B., Özkay, Y., Kaplancıklı, Z.A. (2022). Novel imidazole derivatives as potential aromatase and monoamine oxidase-B inhibitors against breast cancer. New Journal of Chemistry, 46 (16), 7442-7451. 10.1039/d2nj00424k
CR  - Özkay, Y., Evren, A.E., Yurttaş, L. (2022). Synthesis and In Silico Evaluation of Some New 2,4-Disubstituted Thiazole Derivatives. European Journal of Life Sciences, 1 (1), 8-19. 10.55971/ejls.1089425
CR  - Pinho, S.S., Carvalho, S., Cabral, J., Reis, C.A., Gartner, F. (2012). Canine tumors: a spontaneous animal model of human carcinogenesis. Transl Res, 159 (3), 165-172. 10.1016/j.trsl.2011.11.005
CR  - Roskoski Jr, R. (2024). Properties of FDA-approved small molecule protein kinase inhibitors: a 2024 update. Pharmacological research, 107059.
CR  - Saffour, S., Al-Sharabi, A.A., Evren, A.E., Cankiliç, M.Y., Yurttaş, L. (2024). Antimicrobial activity of novel substituted 1,2,4-triazole and 1,3-thiazole derivatives. J Mol Struct, 1295, 136675. 10.1016/j.molstruc.2023.136675
CR  - Sarver, A.L., Makielski, K.M., DePauw, T.A., Schulte, A.J., Modiano, J.F. (2022). Increased risk of cancer in dogs and humans: A consequence of recent extension of lifespan beyond evolutionarily determined limitations? Aging and cancer, 3 (1), 3-19.
CR  - Sharifi, M., Hosseinali, S.H., Saboury, A.A., Szegezdi, E., Falahati, M. (2019). Involvement of planned cell death of necroptosis in cancer treatment by nanomaterials: Recent advances and future perspectives. J Control Release, 299, 121-137. 10.1016/j.jconrel.2019.02.007
CR  - Singh, A., Malhotra, D., Singh, K., Chadha, R., Bedi, P.M.S. (2022). Thiazole derivatives in medicinal chemistry: Recent advancements in synthetic strategies, structure activity relationship and pharmacological outcomes. J Mol Struct, 133479. 10.1016/j.molstruc.2022.133479
CR  - Skora, B., Lewinska, A., Kryshchyshyn-Dylevych, A., Kaminskyy, D., Lesyk, R., Szychowski, K.A. (2022). Evaluation of Anticancer and Antibacterial Activity of Four 4-Thiazolidinone-Based Derivatives. Molecules, 27 (3)10.3390/molecules27030894
CR  - Szychowski, K.A., Kaminskyy, D.V., Leja, M.L., Kryshchyshyn, A.P., Lesyk, R.B., Tobiasz, J., Wnuk, M., Pomianek, T., Gminski, J. (2019). Anticancer properties of 5Z-(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one. Sci Rep, 9 (1), 10609. 10.1038/s41598-019-47177-6
CR  - Tarighati, E., Keivan, H., Mahani, H. (2023). A review of prognostic and predictive biomarkers in breast cancer. Clin Exp Med, 23 (1), 1-16. 10.1007/s10238-021-00781-1
CR  - Tolomeo, M., Simoni, D. (2002). Drug resistance and apoptosis in cancer treatment: development of new apoptosis-inducing agents active in drug resistant malignancies. Curr Med Chem Anticancer Agents, 2 (3), 387-401. 10.2174/1568011024606361
CR  - Wang, Y.-T., Huang, X., Cai, X.-C., Kang, X.-X., Zhu, H.-L. (2024). Synthesis, biological evaluation and molecular docking of thiazole hydrazone derivatives grafted with indole as novel tubulin polymerization inhibitors. J Mol Struct, 1301, 137343. 10.1016/j.molstruc.2023.137343
CR  - Wu, P., Nielsen, T.E., Clausen, M.H. (2015). FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci, 36 (7), 422-439. 10.1016/j.tips.2015.04.005
CR  - Xing, X., Pang, E., Zhao, S., Pan, T., Tan, Q., Wang, B., Song, X., Lan, M. (2024). Cisplatin-appended BODIPY for near infrared II fluorescent and photoacoustic imaging-guided synergistic phototherapy and chemotherapy of cancer. Chinese Chemical Letters, 35 (3), 108467. 10.1016/j.cclet.2023.108467
CR  - Xiong, B., Chen, S., Zhu, P., Huang, M., Gao, W., Zhu, R., Qian, J., Peng, Y., Zhang, Y., Dai, H., Ling, Y. (2019). Design, Synthesis, and Biological Evaluation of Novel Thiazolyl Substituted Bis-pyrazole Oxime Derivatives with Potent Antitumor Activities by Selectively Inducing Apoptosis and ROS in Cancer Cells. Med Chem, 15 (7), 743-754. 10.2174/1573406414666180827112724
CR  - Xiong, L., Zhang, Y., Wang, J., Yu, M., Huang, L., Hou, Y., Li, G., Wang, L., Li, Y. (2024). Novel small molecule inhibitors targeting renal cell carcinoma: Status, challenges, future directions. Eur J Med Chem, 116158.
CR  - Yang, C.Y., Shiranthika, C., Wang, C.Y., Chen, K.W., Sumathipala, S. (2023). Reinforcement learning strategies in cancer chemotherapy treatments: A review. Comput Methods Programs Biomed, 229, 107280. 10.1016/j.cmpb.2022.107280
CR  - Youdim, M.B. (2013). Multi target neuroprotective and neurorestorative anti-Parkinson and anti-Alzheimer drugs ladostigil and m30 derived from rasagiline. Exp Neurobiol, 22 (1), 1-10. 10.5607/en.2013.22.1.1
CR  - Yucel, N.T., Asfour, A.A.R., Evren, A.E., Yazici, C., Kandemir, U., Ozkay, U.D., Can, O.D., Yurttas, L. (2024). Design and synthesis of novel dithiazole carboxylic acid Derivatives: In vivo and in silico investigation of their Anti-Inflammatory and analgesic effects. Bioorg Chem, 144, 107120. 10.1016/j.bioorg.2024.107120
CR  - Yurttas, L., Evren, A.E., AlChaib, H., Temel, H.E., Akalin Ciftci, G. (2024). Synthesis, molecular docking, and molecular dynamic simulation studies of new 1,3,4-thiadiazole derivatives as potential apoptosis inducers in A549 lung cancer cell line. J Biomol Struct Dyn, 1-16. 10.1080/07391102.2023.2300125
CR  - Yurttaş, L., Çavuşoğlu, B.K., Cantürk, Z. (2020). Novel 2-(2-hydrazinyl)thiazole derivatives as chemotherapeutic agents. Synth. Commun., 50 (20), 3072-3079. 10.1080/00397911.2020.1791344
CR  - Yurttaş, L., Evren, A.E., Kubilay, A., Aksoy, M.O., Temel, H.E., Akalın Çiftçi, G. (2023). Synthesis of Some New 1,3,4-Oxadiazole Derivatives and Evaluation of Their Anticancer Activity. ACS Omega,  10.1021/acsomega.3c07776
CR  - Yurttaş, L., Öztürk, Ö., Cantürk, Z. (2019). New Procaspase Activating Compound (PAC-1) Like Molecules as Potent Antitumoral Agents Against Lung Cancer. Lett Drug Des Discov, 16 (6), 645-655. 10.2174/1570180815666180926113040
UR  - https://doi.org/10.30607/kvj.1430771
L1  - https://dergipark.org.tr/en/download/article-file/3703223
ER  -