SYNTHESIS OF THIOUREA DERIVATIVES FROM M-METHOXYCINNAMIC ACID AS ANTIANGIOGENIC CANDIDATE

Authors

  • Juni Ekowati Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
  • Iwan Sahrial Hamid Faculty of Veterinary Medicine, Airlangga University, Surabaya, Indonesia
  • Kholis Amalia Nofianti Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
  • Shigeru Sasaki Institute Medicinal Chemistry, Hoshi University, Tokyo, Japan

DOI:

https://doi.org/10.11113/jt.v81.13410

Keywords:

Microwave irradiation, angiogenic inhibitor, COX-2, EGFR, celecoxib, ADMET profile

Abstract

Microwave-assisted nucleophilic acyl substitution was employed to obtain thiourea derivatives (3a, 3b, 3c) from m-methoxycinnamic acid (1). This synthesis method successfully yielded 60-70% reaction product. In vivo anti-angiogenic evaluation was conducted by chick chorioallantoic membrane model, by which each of the derivative at dose 30, 60, and 90 µg induced by bFGF and compared to celecoxib 60 µg as positive control. It was found that all of the synthesized compound at the tested dose were able to inhibit neovascularization and formation of endothelial cell of new blood vessels by 51-75%. In silico analysis predicted that the anti-angiogenesis mechanism of all the synthesized compounds is through the inhibition of EGFR kinase and COX-2. N atom acts as hydrogen bonding acceptor by residue Gly526 of COX-2. While thiourea moieties of 3a-c have hydrophobic interaction by residues Ser530, Tyr385, and Leu352. In addition, the carbonyl group of thiourea of compound 3a-c inhibit EGFR kinase through the interaction with lys745. The pKCSM data revealed that 3a-c absorbed in intestine by 89-92%, and acut toxicity in rat category 4, suggesting that the compounds show good absorption, and low toxicity. In conclusion, this study successfully synthesized thiourea derivatives, which have anti-angiogenesis activity, tested by CAM model.

Author Biographies

  • Juni Ekowati, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
    Department of Pharmaceutical Chemistry, Secretary, Ass. Prof.
  • Iwan Sahrial Hamid, Faculty of Veterinary Medicine, Airlangga University, Surabaya, Indonesia
    Department of Basic Veterinary Medicine, member, Ass.Prof.
  • Kholis Amalia Nofianti, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
    Department Pharmaceutical Chemistry, member
  • Shigeru Sasaki, Institute Medicinal Chemistry, Hoshi University, Tokyo, Japan
    Institute of Medicinal Chemistry

References

Sahib, H. B., Al-Zubaidy, A. A., Jasim, G. A. 2016. Anti Angiogenic Activity Of Vitex Agnus Castus Methanol Extract In Vivo Study. Iran J Pharm Sci. 12(1): 59-68.

Xu. L., Croix, B. St. 2014. Improving VEGF-targeted Therapies through Inhibition of COX-2/PGE 2 Signaling. Mol Cell Oncol [Internet]. 1(4): e969154. Available from: http://www.tandfonline.com/doi/full/10.4161/23723548.2014.969154.

Kuwano, T., Nakao, S., Yamamoto, H., Tsuneyoshi, M., Yamamoto, T., Kuwano, M., et al. 2004. Cyclooxygenase 2 is a Key Enzyme for Inflammatory Cytokine-induced Angiogenesis. FASEB J [Internet]. 18(2): 300-10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14769824.

Hsu, H. H., Lin, Y. M., Shen, C. Y., Shibu, M. A., Li, S. Y., Chang, S. H., et al. 2017. Prostaglandin E2-induced COX-2 Expressions via EP2 and EP4 Signaling Pathways in Human LoVo Colon Cancer Cells. Int J Mol Sci. 18(6).

Xin, X., Majumder, M., Girish, G. V., Mohindra, V., Maruyama, T., Lala, P. K. 2012. Targeting COX-2 and EP4 to Control Tumor Growth, Angiogenesis, Lymphangiogenesis and Metastasis to the Lungs and Lymph Nodes in a Breast Cancer Model. Lab Investig [Internet]. 92(8): 1115-28.

Available: http:// dx.doi.org/10.1038/labinvest.2012.90.

Abraham Sunshine NYEMLL, Carole, E. siege, Mamaroneck all of NY, [73]. United States Patent 191. 1985;4,552,899.

Evans, T. C., Gavrilovich, E., Mihai, R. C. and Isbasescu, I. EL, Thelen, D., Martin, J. A., Allen, S. M., S. A. S. (12) Patent Application Publication (10) Pub. No.: US 2006/0222585 A1 Figure 1. (2017); 002(15),354.

Newton, H. B. 2009. Bevacizumab: Review of Development, Pharmacology, and Application to Brain Tumors. Clin Med Ther. 1: 1577-97.

Jana, D., Sarkar, D. K., Ganguly, S., Saha, S., Sa, G., Manna, A. K., et al. 2014. Role of Cyclooxygenase 2 (COX-2) in Prognosis of Breast Cancer. Indian J Surg Oncol. 5(1): 59-65.

Grünewald, F. S., Prota, A. E., Giese, A., Ballmer-Hofer, K. 2010. Structure-function Analysis of VEGF Receptor Activation and the Role of Coreceptors in Angiogenic Signaling. Biochim Biophys Acta-Proteins Proteomics [Internet]. 1804(3): 567-80. Available from: http://dx.doi.org/10.1016/j.bbapap.2009.09.002.

Sun, S., Zhang, J., Wang, N., Kong, X., Fu, F., Wang, H., et al. 2017. Design and Discovery of Quinazoline- and Thiourea-Containing Sorafenib Analogs as EGFR and VEGFR-2 Dual TK Inhibitors. Molecules [Internet]. 23(1): 24. Available from: http://www.mdpi.com/1420-3049/23/1/24.

Kumar, B. N. P., Rajput, S., Dey, K. K., Parekh, A., Das, S., Mazumdar, A., et al. 2013 Celecoxib Alleviates Tamoxifen-instigated Angiogenic Effects by ROS-dependent VEGF/VEGFR2 Autocrine Signaling. BMC Cancer [Internet]. 13(1): 273. Available from: http://bmccancer.biomedcentral.com/articles/10.1186/ 1471-2407-13-273.

Wu, G. F., Luo, J., Rana, J. S., Laham, R., Sellke, F. W., Li, J. 2006. Involvement of COX-2 in VEGF-induced Angiogenesis via P38 and JNK Pathways in Vascular Endothelial Cells. Cardiovasc Res. 69(2): 512-9.

Ekowati, J., Hardjono, S., Hamid, I. S. 2015. Ethyl p-methoxycinnamate from Kaempferia Galanga Inhibits Angiogenesis Through Tyrosine Kinase. Universa Med. 34(1): 43-51.

Umar, M. I., Asmawi, M. Z., Sadikun, A., Atangwho, I. J., Yam, M. F., Altaf, R., et al. 2012. Bioactivity-guided Isolation of Ethyl-p-methoxycinnamate, An Anti-Inflammatory Constituent, from Kaempferia Galanga L. Extracts. Molecules. 17(7): 8720-34.

Sulistyowaty, M. I., Nugroho, A. E., Putra, G. S., Ekowati, J., Budiati, T. 2016. Syntheses, Molecular Docking Study and Anticancer Activity Examination of P-Methoxycinnamoyl Hydrazides. Int J Pharm Clin Res. 8(6): 623-627.

Manoharan, S., Rejitharaji, T., Prabhakar, M. M., Manimaran, A., Singh, R. B. 2014. Modulating Effect of Ferulic Acid on NF-κB COX-2 and VEGF Expression Pattern During 7, 12-Dimethylbenz(a)anthracene Induced Oral Carcinogenesis. Open Nutraceuticals J. 7(2007): 33-8.

Peng, C. C., Chyau, C. C., Wang, H. E., Chang, C. H., Chen, K. C., Chou, K. Y., et al. 2013. Cytotoxicity of Ferulic Acid on T24 Cell Line Differentiated by Different Microenvironments. Biomed Res Int. Article ID 579859.

Gunasekaran, S., Venkatachalam, K., Namasivayam, N. 2018. Anti-inflammatory and Anticancer Effects of p-methoxycinnamic Acid, an Active Phenylpropanoid, against 1,2-dimethylhydrazine-induced Rat Colon Carcinogenesis. Mol Cell Biochem [Internet]. 0(0): 1-13. Available from: http://dx.doi.org/10.1007/s11010-018-3398-5.

Ekowati, J., Tejo, B. A., Sasaki, S., Highasiyama, K., Sukardiman, Siswandono, et al. 2012. Structure Modification of Ethyl p-methoxycinnamate and their Bioassay as Chemopreventive Agent against Mice’s Fibrosarcoma. Int J Pharm Pharm Sci. 4(SUPPL. 3): 528-532.

Shoaib, M., Shafiullah, Ayaz, M., Tahir, M. N., Shah, S. W. A. 2016. Synthesis, Characterization, Crystal Structures, Analgesic and Antioxidant Activities of Thiourea Derivatives. J Chem Soc Pakistan. 38(3): 479-486.

Ghorab, M. M., El-Gaby, M. S. A., Alsaid, M. S., Elshaier, Y. A. M. M., Soliman, A. M., El-Senduny, F. F., et al. 2017. Novel Thiourea Derivatives Bearing Sulfonamide Moiety as Anticancer Agents Through COX-2 Inhibition. Anticancer Agents Med Chem [Internet]. 17(10): 1411-1425. Available from: http://www.eurekaselect.com/151128/article.

van Schijndel, J., Canalle, L. A., Molendijk, D., Meuldijk, J. 2017. The Green Knoevenagel Condensation: Solvent-free Condensation of Benzaldehydes. Green Chem Lett Rev. 10(4): 404-11.

Lipinski, C. A. 2016. Rule of Five in 2015 and Beyond: Target and Ligand Structural Limitations, Ligand Chemistry Structure and Drug Discovery Project Decisions. Adv Drug Deliv Rev [Internet]. 101: 34-41. Available from: http://dx.doi.org/10.1016/j.addr.2016.04.029.

Prabhu, K., Mahto, M. K., Gopalakrishnan, V. K. 2014. Virtual Screening, Molecular Docking and Molecular Dynamics Studies for Discovery of Novel Vegfr-2 Inhibitors. International Journal of Pharmaceutical and Clinical Research. 6(3): 221-229.

Coskun, G. l. P., Djikic, T., Hayal, T. B., Turkel, N., Yelekçi, K.¸ Sahin, F., and Küçükgüzel, S. G. 2018. Synthesis, Molecular Docking and Anticancer Activity of Diflunisal Derivatives as Cyclooxygenase Enzyme Inhibitors. Molecule. 23(1969): 1-19. doi:10.3390/molecules23081969.

Pineiro, M., Dias, L., Damas, L., Aquino, G., Calvete, M. and Pereira, M. 2016. Microwave Irradiation as a Sustainable Tool for Catalytic Carbonylation Reactions. Inorganica Chimica Acta. 455: 364-377.

Pires, D. E. V., Blundell, T. L., Ascher, D. B. 2015. pkCSM Predicting Small-molecule Pharmacokinetic and Toxicity Properties Using Graph-based Signatures. J Med Chem. 58(9): 4066-72.

Ribatti, D. 2010. The Chick Embryo Chorioallantoic Membrane as an In Vivo Assay to Study Antiangiogenesis. Pharmaceuticals. 3(3): 482-513.

Salcedo, R., Zhang, X., Young, H. A., Michael, N., Wasserman, K., Ma, W. H., et al. 2003. Angiogenic Effects of Prostaglandin E2are Mediated by up-regulation of CXCR4 on Human Microvascular Endothelial Cells. Blood. 102(6): 1966-77.

Majima, M., Hayashi, I., Muramatsu, M., Katada, J., Yamashina, S., Katori, M. 2000. Cyclo-oxygenase-2 Enhances Basic Fibroblast Growth Factor-induced Angiogenesis through Induction of Vascular Endothelial Growth Factor in Rat Sponge Implants. Br J Pharmacol. 130(3): 641-9.

Cheng, H-W., Chen, Y-F., Wong, J-M., Weng, C-W., Chen, H-Y., Yu, S-L., et al. 2017. Cancer Cells Increase Endothelial Cell Tube Formation and Survival by Activating the PI3K/Akt Signalling Pathway. J Exp Clin Cancer Res [Internet]. 36(1): 27. Available from: http://jeccr.biomedcentral.com/articles/10.1186/s13046-017-0495-3.

Burri, P. H., Hlushchuk, R., Djonov, V. 2004. Intussusceptive Angiogenesis: Its Emergence, Its Characteristics, and Its Significance. Dev Dyn. 231(3): 474-88.

Niu, G., Chen, X. 2010. Vascular Endothelial Growth Factor as an Anti-angiogenic Target for Cancer therapy. Curr Drug Targets [Internet]. 11(8): 1000-17. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3617502&tool=pmcentrez&rendertype=abstract

Leahy, K., Koki, A., Masferrer, J. 2000. Role of Cyclooxygenases in Angiogenesis. Curr Med Chem [Internet]. 7(11): 1163-70. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=0929-8673&volume=7&issue=11&spage=1163.

Valverde, A., Peñarando, J., Cañas, A., López-Sánchez, L. M., Conde, F., Hernández, V., et al. 2015. Simultaneous Inhibition of EGFR/VEGFR and Cyclooxygenase-2 Targets Stemness-related Pathways in Colorectal Cancer Cells. PLoS One [Internet]. 10(6): 1-23. Available from: http://dx.doi.org/10.1371/journal.pone.0131363.

Tabernero, J. 2007. The Role of VEGF and EGFR Inhibition: Implications for Combining Anti-VEGF and Anti-EGFR Agents. Mol Cancer Res [Internet]. 5(3): 203-20. Available from: http://mcr.aacrjournals.org/cgi/doi/10.1158/1541-7786.MCR-06-0404.

Downloads

Published

2019-06-25

Issue

Vol. 81 No. 4: July 2019

Section

Science and Engineering

License

Copyright of articles that appear in Jurnal Teknologi belongs exclusively to Penerbit Universiti Teknologi Malaysia (Penerbit UTM Press). This copyright covers the rights to reproduce the article, including reprints, electronic reproductions, or any other reproductions of similar nature.

How to Cite

SYNTHESIS OF THIOUREA DERIVATIVES FROM M-METHOXYCINNAMIC ACID AS ANTIANGIOGENIC CANDIDATE. (2019). Jurnal Teknologi, 81(4). https://doi.org/10.11113/jt.v81.13410