2-Amino-tiyazol Grubu İçeren 5-Florourasil Dimerinin Klik Tepkimesi Yoluyla Sentezi

Year 2021, , 315 - 332, 31.01.2021

Gizem Öztürkoğlu Emriye Ay , Hüseyin Alp Kadir Ay

https://doi.org/10.31202/ecjse.789749

Abstract

Kanserin dünyada insan ölümlerinin nedeni olan hastalıkların başında olmasından dolayı, antikanser ya da daha az yan etkili yeni bileşiklerin sentezi oldukça önemlidir. 5-Florourasil (5-FU) kemoterapi için kullanılan bileşiklerin en eskilerinden biridir. Bu çalışmada, potansiyel antikanser özelliklerine sahip 1,2,3-triazol köprüsü içeren bileşik 4, moleküler hibridizasyon yaklaşımı kullanılarak 5-FU ve 2-aminotiyazolün klik tepkimesi yoluyla sentezlendi. Yeni bileşiğin yapı aydınlatması, FTIR, 1H, 13C, 19F, COSY, HSQC, HMBC ve TOF-MS gibi modern spektroskopik yöntemler kullanılarak gerçekleştirildi.

Keywords

5-FU, klik tepkimesi, triazol, antikanser, moleküler hibridizasyon

Synthesis of 5-Fluorouracil Dimer Containing 2-Amino-thiazole Group via Click Reaction

Abstract

Since cancer is one of the leading diseases that cause human deaths in the world, the synthesis of anticancer or new compounds with fewer side effects is important. 5-Fluorouracil (5-FU) is one of the oldest compounds used for chemotherapy. In this study, 1,2,3-triazole bridge containing compound 4, which could have potential anticancer properties, was synthesized via the click reaction from the 5-FU and 2-aminothiazole using the molecular hybridization approach. The structural elucidation of the new compound was carried out using modern spectroscopic methods such as FTIR, 1H, 13C, 19F, COSY, HSQC, HMBC and TOF-MS.

Keywords

5-FU, click reaction, triazole, anticancer, molecular hybridization

References

• https://www.who.int/news-room/fact-sheets/detail/cancer. [Ziyaret tarihi 12.07.2020].
• Şentürk, A. and Şentürk, Z. K., "Yapay Sinir Ağları İle Göğüs Kanseri Tahmini", El-Cezeri Journal of Science and Engineering, 2016, 3 (2): 345-350.
• Pan, X., Wang, C., Wang, F., Li, P., Hu, Z., Shan, Y. and Zhang, J., "Development of 5-Fluorouracil derivatives as anticancer agents", Current Medicinal Chemistry, 2011, 18 (29): 4538-4556.
• Álvarez, P., Marchal, J. A., Boulaiz, H., Carrillo, E., Vélez, C., Rodríguez-Serrano, F., Melguizo, C., Prados, J., Madeddu, R. and Aranega, A., "5-Fluorouracil derivatives: a patent review", Expert Opinion on Therapeutic Patents, 2012, 22 (2): 107-123.
• Semakov, A., Blinkov, A., Gaenko, G., Vostrova, A. and Molotkovsky, J., "Synthesis and properties of lipophilic derivatives of 5-fluorouracil", Russian Journal of Bioorganic Chemistry, 2013, 39 (3): 299-305.
• Yu, B., Qi, P.-P., Shi, X.-J., Huang, R., Guo, H., Zheng, Y.-C., Yu, D.-Q. and Liu, H.-M., "Efficient synthesis of new antiproliferative steroidal hybrids using the molecular hybridization approach", European Journal of Medicinal Chemistry, 2016, 117: 241-255.
• Decker, M., "Design of hybrid molecules for drug development", Elsevier, ISBN: 9780081010112, Chennai, India, (2017).
• Viegas-Junior, C., Danuello, A., Da Silva Bolzani, V., Barreiro, E. J. and Fraga, C. A. M., "Molecular hybridization: a useful tool in the design of new drug prototypes", Current Medicinal Chemistry, 2007, 14 (17): 1829-1852.
• Awolade, P., Cele, N., Kerru, N. and Singh, P., "Synthesis, antimicrobial evaluation, and in silico studies of quinoline-1H-1,2,3-triazole molecular hybrids", Molecular diversity, 2020: 1-18.
• Halay, E., Ay, E., Şalva, E., Ay, K. and Karayıldırım, T., "Synthesis of triazolylmethyl-linked nucleoside analogs via combination of azidofuranoses with propargylated nucleobases and study on their cytotoxicity", Chemistry of Heterocyclic Compounds, 2018, 54 (2): 158-166.
• Halay, E., Ay, E., Şalva, E., Ay, K. and Karayıldırım, T., "Syntheses of 1,2,3-triazole-bridged pyranose sugars with purine and pyrimidine nucleobases and evaluation of their anticancer potential", Nucleosides, Nucleotides and Nucleic Acids, 2017, 36 (9): 598-619.
• Ay, K., Ispartaloğlu, B., Halay, E., Ay, E., Yaşa, İ. and Karayıldırım, T., "Synthesis and antimicrobial evaluation of sulfanilamide-and carbohydrate-derived 1,4-disubstitued-1,2,3-triazoles via click chemistry", Medicinal Chemistry Research, 2017, 26 (7): 1497-1505.
• Halay, E., "1,4-disübstitüe-1,2,3-triazol halkası içeren pürin ve pirimidin esaslı yeni nükleozitlerin klik reaksiyonu yoluyla sentezi", Doktora Tezi, Celal Bayar Üniversitesi Fen Bilimleri Enstitüsü, (2014).
• Tan, A., "Novel 1, 2, 3-triazole compounds: Synthesis, In vitro xanthine oxidase inhibitory activity, and molecular docking studies", Journal of Molecular Structure, 2020: 128060.
• Shmalenyuk, E. R., Chernousova, L. N., Karpenko, I. L., Kochetkov, S. N., Smirnova, T. G., Andreevskaya, S. N., Chizhov, A. O., Efremenkova, O. V. and Alexandrova, L. A., "Inhibition of Mycobacterium tuberculosis strains H37Rv and MDR MS-115 by a new set of C5 modified pyrimidine nucleosides", Bioorganic & Medicinal Chemistry, 2013, 21 (17): 4874-4884.
• Horn, C.-M., Aucamp, J., Smit, F. J., Seldon, R., Jordaan, A., Warner, D. F. and N’da, D. D., "Synthesis and in vitro antimycobacterial and antileishmanial activities of hydroquinone-triazole hybrids", Medicinal Chemistry Research, 2020:
• De Souza, T. B., Raimundo, P. O. B., Andrade, S. F., Hipólito, T. M. M., Silva, N. C., Dias, A. L. T., Ikegaki, M., Rocha, R. P., Coelho, L. F. L. and Veloso, M. P., "Synthesis and antimicrobial activity of 6-triazolo-6-deoxy eugenol glucosides", Carbohydrate Research, 2015, 410: 1-8.
• Aher, N. G., Pore, V. S., Mishra, N. N., Kumar, A., Shukla, P. K., Sharma, A. and Bhat, M. K., "Synthesis and antifungal activity of 1,2,3-triazole containing fluconazole analogues", Bioorganic & Medicinal Chemistry Letters, 2009, 19 (3): 759-763.
• Lu, Y. and Gervay-Hague, J., "Synthesis of C-4 and C-7 triazole analogs of zanamivir as multivalent sialic acid containing scaffolds", Carbohydrate Research, 2007, 342 (12-13): 1636-1650.
• Giffin, M. J., Heaslet, H., Brik, A., Lin, Y.-C., Cauvi, G., Wong, C.-H., Mcree, D. E., Elder, J. H., Stout, C. D. and Torbett, B. E., "A copper (I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant", Journal of Medicinal Chemistry, 2008, 51 (20): 6263-6270.
• Vatmurge, N. S., Hazra, B. G., Pore, V. S., Shirazi, F., Chavan, P. S. and Deshpande, M. V., "Synthesis and antimicrobial activity of β-lactam–bile acid conjugates linked via triazole", Bioorganic & Medicinal Chemistry Letters, 2008, 18 (6): 2043-2047.
• Raj, R., Sharma, V., Hopper, M. J., Patel, N., Hall, D., Wrischnik, L. A., Land, K. M. and Kumar, V., "Synthesis and preliminary in vitro activity of mono-and bis-1H-1,2,3-triazole-tethered β-lactam–isatin conjugates against the human protozoal pathogen Trichomonas vaginalis", Medicinal Chemistry Research, 2014, 23 (8): 3671-3680.
• Singh, J., Sharma, S., Saxena, A., Nepali, K. and Bedi, P. M. S., "Synthesis of 1,2,3-triazole tethered bifunctional hybrids by click chemistry and their cytotoxic studies", Medicinal Chemistry Research, 2013, 22 (7): 3160-3169.
• Altimari, J. M., Niranjan, B., Risbridger, G. P., Schweiker, S. S., Lohning, A. E. and Henderson, L. C., "Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide", Bioorganic & Medicinal Chemistry Letters, 2014, 24 (21): 4948-4953.
• Wilkinson, B. L., Bornaghi, L. F., Houston, T. A., Innocenti, A., Supuran, C. T. and Poulsen, S.-A., "A novel class of carbonic anhydrase inhibitors: glycoconjugate benzene sulfonamides prepared by “click-tailing”", Journal of Medicinal Chemistry, 2006, 49 (22): 6539-6548.
• Kumar, K., Sagar, S., Esau, L., Kaur, M. and Kumar, V., "Synthesis of novel 1H-1,2,3-triazole tethered C-5 substituted uracil-isatin conjugates and their cytotoxic evaluation", European Journal of Medicinal Chemistry, 2012, 58: 153-159.
• Khalifa, M. E., "Recent developments and biological activities of 2-aminothiazole derivatives", Acta Chimica Slovenica, 2018, 65 (1): 1-22.
• Göblyös, A., Santiago, S. N., Pietra, D., Mulder-Krieger, T., Künzel, J. v. F. D., Brussee, J. and Ijzerman, A. P., "Synthesis and biological evaluation of 2-aminothiazoles and their amide derivatives on human adenosine receptors. Lack of effect of 2-aminothiazoles as allosteric enhancers", Bioorganic & Medicinal Chemistry, 2005, 13 (6): 2079-2087.
• Hang, P. C. and Honek, J. F., "Electronic structure calculations on the thiazole-containing antibiotic thiostrepton: molecular mechanics, semi-empirical and ab initio analyses", Bioorganic&Medicinal Chemistry Letters, 2005, 15 (5): 1471-1474.
• Beuchet, P., Varache-Lembège, M., Neveu, A., Léger, J.-M., Vercauteren, J., Larrouture, S., Deffieux, G. and Nuhrich, A., "New 2-sulfonamidothiazoles substituted at C-4: synthesis of polyoxygenated aryl derivatives and in vitro evaluation of antifungal activity", European Journal of Medicinal Chemistry, 1999, 34 (9): 773-779.
• Geronikaki, A. and Theophilidis, G., "Synthesis of 2-(aminoacetylamino) thiazole derivatives and comparison of their local anaesthetic activity by the method of action potential", European Journal of Medicinal Chemistry, 1992, 27 (7): 709-716.
• Prasanna, D., Kavitha, C., Vinaya, K., Ranganatha, S., Raghavan, S. C. and Rangappa, K., "Synthesis and Identification of a new class of antileukemic agents containing 2-(arylcarboxamide)-(S)-6-amino-4,5,6,7-tetrahydrobenzo [d] thiazole", European Journal of Medicinal Chemistry, 2010, 45 (11): 5331-5336.
• Bolos, C., Papazisis, K., Kortsaris, A., Voyatzi, S., Zambouli, D. and Kyriakidis, D., "Antiproliferative activity of mixed-ligand dien-Cu (II) complexes with thiazole, thiazoline and imidazole derivatives", Journal of Inorganic Biochemistry, 2002, 88 (1): 25-36.
• Guo, X., Ma, X., Yang, Q., Xu, J., Huang, L., Jia, J., Shan, J., Liu, L., Chen, W. and Chu, H., "Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium channel inhibitors (part I)", European Journal of Medicinal Chemistry, 2014, 81: 89-94.
• Deb, P. K., Kaur, R., Chandrasekaran, B., Bala, M., Gill, D., Kaki, V. R., Akkinepalli, R. R. and Mailavaram, R., "Synthesis, anti-inflammatory evaluation, and docking studies of some new thiazole derivatives", Medicinal Chemistry Research, 2014, 23 (6): 2780-2792.
• He, Y., Zeng, L.-F., Yu, Z.-H., He, R., Liu, S. and Zhang, Z.-Y., "Bicyclic benzofuran and indole-based salicylic acids as protein tyrosine phosphatase inhibitors", Bioorganic & Medicinal Chemistry, 2012, 20 (6): 1940-1946.
• Green Samuel, A. and Jebasingh, B., "Facile Synthesis of 1,4-Disubstituted 1,2,3-Triazoles Using Tetraaza-coordinated Copper (II) Complexes as Efficient Catalysts", ChemistrySelect, 2020, 5 (2): 645-648.