Synthesis and cytotoxicity evaluation of thiazole conjugated amino acid derivatives
Main Article Content
Abstract
This paper presents the three-step synthesis and cytotoxicity evaluation of the thiazole-conjugated amino acid derivatives. Starting from the commercially available benzophenone and thiourea, the thiazole structure was successfully constructed bearing the free amino groups at the C-2 position, which was then coupled with the carboxyl functionality of N-Boc L-phenylalanine, N-Boc L-proline and N-Boc L-tryptophane using CDI as the coupling reagent under mild basic conditions to provide the hybrid thiazole/N-Boc amino acid derivatives 5a-c. Finally, the acidic promoted deprotection of the Boc groups afforded the desired hybrid thiazole/amino acid derivatives 6a-c in reasonable total yields. Cytotoxicity assays indicated that the hybrids thiazole/L-proline (6a) and thiazole/L-tryptophan (6c) exhibited rather good cytotoxicity on the cervical cancer cell line (IC50 =18.86 and 18.25 µM, respectively). Notably, compound 5a having the thiazole conjugated with unprotected N-Boc L-phenylalanine showed very good activity towards the lung cancer (IC50 = 15.72 µM), the cervical cancer (IC50 = 8.98 µM) and the breast cancer cell lines (IC50 = 8.07 µM), which were 1.3-, 1.2- and 2.5-fold, respectively, stronger activity than 5-FU (IC50 = 20.73, 10.67 and 20.43 µM, respectively).
Article Details

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
References
Abraham, J., & Staffurth, J. (2016). Hormonal therapy for cancer. Medicine, 44(1), 30-33.
Abedi-Jazini, Z., Safari, J., Zarnegar, Z., & Sadeghi, M. (2018). A simple and efficient method for the synthesis of 2-aminothiazoles under mild conditions. Polycyclic Aromatic Compounds, 38(3), 231-235.
Ayati, A., Emami, S., Moghimi, S., & Foroumadi, A. (2019). Thiazole in the targeted anticancer drug discovery. Medicinal Chemistry, 11(15), 1929–1952.
Alizadeh, S. R., & Hashemi, S. M. (2021). Development and therapeutic potential of 2-aminothiazole derivatives in anticancer drug discovery. Medicinal Chemistry Research, 30(4), 771–806.
Barrett, G. C., & Lubec, G. (1991). Amino acids: Holding centre stage more strongly than ever, and continuing to spring surprises. Amino Acids, 1(1), 1–6.
Baronzio, G., Parmar, G., Ballerini, M., Szasz, A., Baronzio, M., & Cassutti, V. (2014). A brief overview of hyperthermia in cancer treatment. J. Integr. Oncol., 3(115), 2.
Bui, H. T. B., Ha, Q. T. K., Oh, W. K., Vo, D. D., Chau, Y. N. T., Tu, C. T. K., Pham, E. C., Tran, P. T., Tran, L. T., & Van Mai, H. (2016). Microwave assisted synthesis and cytotoxic activity evaluations of new benzimidazole derivatives. Tetrahedron Letters, 57(8), 887-891.
Bui, H. T. B., Do, K. M., Nguyen, H. T. D., Van Mai, H., Danh, T. L. D., & Morita, H. (2021). Efficient one-pot tandem synthesis and cytotoxicity evaluation of 2, 3-disubstituted quinazolin-4 (3H)-one derivatives. Tetrahedron, 98, 132426.
Bui, H. T. B., Do, K. M., Hong, Q. V., Le, H. T., Hnin, S. Y. Y., Tran, D. Q.,Van Mai, H., Nguyen, T. T. T., Mai, T. T. K., & Morita, H. (2024). Solvent-free strategy for facile synthesis and cytotoxicity evaluation of benzimidazole derivatives. Tetrahedron, 156, 133940.
Conti, P., Tamborini, L., Pinto, A., Blondel, A., Minoprio, P., Mozzarelli, A., & De Micheli, C. (2011). Drug discovery targeting amino acid racemases. Chemical Reviews, 111(11), 6919–6946.
Deo, S. V. S., Sharma, J., & Kumar, S. (2022). GLOBOCAN 2020 Report on Global Cancer Burden: Challenges and Opportunities for Surgical Oncologists. Annals Surgical Oncology, 29(11), 6497–6500.
Hue, B. T. B., Nguyen, H. M., Van Hieu, M., Thanh, D. L. D., Son, N. H., De, T. Q., & Morita, H. (2019). Facile sodium metabisulfite mediated synthesis of 1, 2-disubstituted benzimidazoles and cytotoxicity evaluation. Heterocycles, 98(5), 650-665.
Ivkovic, J., Lembacher-Fadum, C., & Breinbauer, R. (2015). A rapid and efficient one-pot method for the reduction of N-protected α-amino acids to chiral α-amino aldehydes using CDI/DIBAL-H. Organic & Biomolecular Chemistry, 13(42), 10456-10460.
Kirkwood, J. M., Butterfield, L. H., Tarhini, A. A., Zarour, H., Kalinski, P., & Ferrone, S. (2012). Immunotherapy of cancer in 2012. CA: A Cancer Journal for Clinicians, 62(5), 309-335.
Kerru, N., Singh, P., Koorbanally, N., Raj, R., & Kumar, V. (2017). Recent advances (2015–2016) in anticancer hybrids. European Journal of Medicinal Chemistry, 142, 179-212.
Kerr, K. M., Bibeau, F., Thunnissen, E., Botling, J., Ryška, A., Wolf, J., Öhrling, K., Burdon, P., Malapelle, U., & Büttner, R. (2021). The evolving landscape of biomarker testing for non-small cell lung cancer in Europe. Lung Cancer (Amsterdam, Netherlands), 154, 161–175.
Love, R. R., Leventhal, H., Easterling, D. V., & Nerenz, D. R. (1989). Side effects and emotional distress during cancer chemotherapy. Cancer, 63(3), 604-612.
Le, H. T., Do, K. M., Nguyen, Q. P., Doan, C. N. M., Nguyen, N. A., Phan, T. T., Tran, X. T. C., Ha, Q. T. K., Tran, D. Q., Morita, H., & Bui, H. T. B. (2024). Syntheses and cytotoxicities of quinazolinone-based conjugates. Chemical and Pharmaceutical Bulletin, 72(1), 61-67.
Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65(1-2), 55-63.
Mak, J. Y., Xu, W., & Fairlie, D. P. (2017). Thiazoles in peptides and peptidomimetics. Peptidomimetics I, 235-266.
Métro, T. X., Martinez, J., & Lamaty, F. (2017). 1, 1′-Carbonyldiimidazole and mechanochemistry: a shining green combination. ACS Sustainable Chemistry & Engineering, 5(11), 9599-9602.
Quy, N. P., Hue, B. T. B., Do, K. M., Quy, H. T. K., De, T. Q., Phuong, T. T. B., Trang, P. C., Quoc, N. C., & Morita, H. (2022). Design, synthesis and cytotoxicity evalufation of substituted benzimidazole conjugated 1, 3, 4-oxadiazoles. Chemical and Pharmaceutical Bulletin, 70(6), 448-453.
Sawyers, C. (2004). Targeted cancer therapy. Nature, 432(7015), 294-297.
Willett, C. G., Czito, B. G., & Tyler, D. S. (2007). Intraoperative radiation therapy. Journal of Clinical Oncology, 25(8), 971-977.
Wu, G. (2009). Amino acids: metabolism, functions, and nutrition. Amino Acids, 37, 1-17.
Waks, A. G., & Winer, E. P. (2019). Breast Cancer Treatment: A Review. JAMA, 321(3), 288–300.
Zugazagoitia, J., Guedes, C., Ponce, S., Ferrer, I., Molina-Pinelo, S., & Paz-Ares, L. (2016). Current challenges in cancer treatment. Clinical Therapeutics, 38(7), 1551-1566.