Abstract:

The present study employed Ultra sound technique to prepare three novel organic compounds. These compounds share a structural similarity with curcumin (A). Specifically, the compounds included the unsubstituted form (B), a 6-OMe-substituted derivative (C), and a 5-Br-substituted derivative (D). The study examined the potential efficacy of selected compounds against kidney cancer in mice through molecular docking approaches. Docking studies revealed that these compounds exhibited strong interactions with four key enzymes involved in inflammation: TNF-alpha, COX-2, IL-6, and LOX-2. Notably, these compounds demonstrated the lowest (most negative) ΔG values, indicating effective inhibition of these enzymes. The results confirmed that the synthesized compounds displayed substantial binding affinity and inhibitory effects on these enzymes. Following molecular docking analysis, an in vivo study was carried out using 90 male mice, randomly assigned to six groups (5 per group). The control group received a standard diet and distilled water, while groups 2 through 6 were administered intraperitoneal injections of N-Nitrosodimethylamine (NDMA) at a dose of 60 mg/kg for two months to induce renal carcinogenesis. Subsequently, groups 3 to 6 received additional intraperitoneal treatments with compounds A, B, C, and D at doses of (0.5, 1.0, and 1.5) mg/kg for 21 consecutive days. Biochemical assessments indicated that compound C exerted significant anticancer activity, demonstrated by a marked reduction in TNF-α levels and inhibition of COX-2, IL-6, and LOX-2 enzymes. These molecular changes were associated with amelioration of renal cancer-induced damage. Histopathological examination further confirmed the therapeutic efficacy of compound C, revealing complete regression of renal tumors.

References:

1.    Al-Sabawi, A. H., Younis, S. A., 2022, Synthesis of some new curcumin derivatives. In AIP Conference Proceedings (Vol. 2394, No. 1). AIP Publishing.  doi:10.1063/5.0121197.

2.    Tomeh, M. A., Hadianamrei, R., Zhao, X., 2019, A review of curcumin and its derivatives as anticancer agents. International journal of molecular sciences, 20(5), 1033.  doi:10.3390/ijms20051033.

3.    Khalaf, K. A., Omar, A. O., 2023, Green Synthesis and Spectroscopic Study of New Heterocyclic Compounds Derived from Ethyl Coumarilate. African Journal of Advanced Pure and Applied Sciences (AJAPAS), 281-289.

4.    D’arcy, M. S., 2019, Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell biology international, 43(6), 582-592.  doi:10.1002/cbin.11137.

5.    Ma, J., Waxman, D. J., 2008, Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Molecular cancer therapeutics, 7(12), 3670-3684.  doi: 10.1158/1535-7163.MCT-08-0715.

6.    Makovec, T., 2019, Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiology and oncology, 53(2), 148. doi: 10.2478/raon-2019-0018. doi:10.2478/raon-2019-0018.

7.    Thoeny, H. C., Ross, B. D., 2010, Predicting and monitoring cancer treatment response with diffusion‐weighted MRI. Journal of Magnetic Resonance Imaging, 32(1), 2-16.  doi:10.1002/jmri.22167.

8.    Zaahkouk, S. M., Aboul-Ela, E. I., Ramadan, M. A., Bakry, S., Mhany, B. M., 2015, Anti-carcinogenic activity of methanolic extract of fennel seeds (Foeniculum vulgare) against breast, colon, and liver cancer cells. Int. J. Adv. Res, 3(5), 1525-1537.

9.    Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., Jemal, A., 2018, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 68(6), 394-424.  doi:10.3322/caac.21492.

10.    Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., Bray, F., 2021, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 71(3), 209-249.  doi:10.3322/caac.21660.

11.    Napiórkowska, M., Cieślak, M., Kaźmierczak-Barańska, J., Królewska-Golińska, K., Nawrot, B., 2019, Synthesis of new derivatives of benzofuran as potential anticancer agents. Molecules, 24(8), 1529.  doi:10.3390/molecules24081529.

12.    Abedinifar, F., Farnia, S. M. F., Mahdavi, M., Nadri, H., Moradi, A., Ghasemi, J. B., Foroumadi, A., 2018, Synthesis and cholinesterase inhibitory activity of new 2-benzofuran carboxamide-benzylpyridinum salts. Bioorganic chemistry, 80, 180-188.  doi:10.1016/j.bioorg.2018.06.006.

13.    Kossakowski, J., Krawiecka, M., Kuran, B., Stefańska, J., Wolska, I., 2010, Synthesis and preliminary evaluation of the antimicrobial activity of selected 3-benzofurancarboxylic acid derivatives. Molecules, 15(7), 4737-4749.  doi:10.3390/molecules15074737.

14.    Sehgal, S. A., 2017, Pharmacoinformatics and molecular docking studies reveal potential novel Proline Dehydrogenase (PRODH) compounds for Schizophrenia inhibition. Medicinal Chemistry Research, 26, 314-326. doi:10.1007/s00044-016-1752-2.

15.    Jiang, Q., Matsuzaki, Y., Li, K., Uitto, J., 2006, Transcriptional regulation and characterization of the promoter region of the human ABCC6 gene. Journal of investigative dermatology, 126(2), 325-335.  doi:10.1038/sj.jid.5700065.

16.    Khalaf, A. K., Omar, O. A., 2023, Synthesis, Pharmacological Evaluation, and Docking Studies of Ethyl Coumarilate Derivatives as Potential Anti-bladder Cancer in a Mouse Model. International Journal of Drug Delivery Technology, 13(4), 1548-1556. doi:10.9734/irjpac/2022/v23i6791.

17.    Ladokun, O. A., Abiola, A., Okikiola, D., Ayodeji, F., 2018, GC-MS and molecular docking studies of Hunteria umbellata methanolic extract as a potent anti-diabetic. Informatics in Medicine Unlocked, 13, 1-8.  doi:10.1016/j.imu.2018.08.001.

18.    Odhar, H. A., Hashim, A. F., Ahjel, S. W., Humadi, S. S., 2023, Molecular docking and dynamics simulation analysis of the human FXIIa with compounds from the Mcule database. Bioinformation, 19(2), 160.  doi:10.6026/97320630019160.

19.    Hassan, H. A., 2015, Synthesis of Some Benzofuran-based Pyrazoline, Isoxazoline, Pyrmidine, Cyclohexenone and Indazole Derivatives. Iraqi National Journal of Chemistry, 15(1), 12-26.

20.    Gold, S. A., Margulis, V., 2023, Carcinogenic effects of nitrosodimethylamine (NDMA) contamination in ranitidine: defining the relationship with renal malignancies. JU Open Plus, 1(10), e00053.  doi:10.1097/JU9.0000000000000058.

21.    Hard, G. C., 1986, Experimental models for the sequential analysis of chemically-induced renal carcinogenesis. Toxicologic pathology, 14(1), 112-122.  doi:10.1177/019262338601400114.

22.    Erhirhie, E. O., Ekene, N. E., Ajaghaku, D. L., 2014, Guidelines on dosage calculation and stock solution preparation in experimental animals' studies. Journal of Natural Sciences Research, 4(18): 100-106.

23.    Brown, A. M., 2005, A new software for carrying out one-way ANOVA post hoc tests. Computer methods and programs in biomedicine, 79(1), 89-95.  doi:10.1016/j.cmpb.2005.02.007.

24.    Ho, M. Y., Tang, S. J., Chuang, M. J., Cha, T. L., Li, J. Y., Sun, G. H., Sun, K. H., 2012, TNF-α induces epithelial–mesenchymal transition of renal cell carcinoma cells via a GSK3β-dependent mechanism. Molecular cancer research, 10(8), 1109-1119.  doi:10.1158/1541-7786.MCR-12-0160.

25.    Ronca, R., Van Ginderachter, J. A., Turtoi, A., 2018, Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes. Current Opinion in Oncology, 30(1), 45-53.  doi:10.1097/CCO.0000000000000420.

26.    Keibel, A., Singh, V., Sharma, M. C., 2009, Inflammation, microenvironment, and the immune system in cancer progression. Current pharmaceutical design, 15(17), 1949-1955. h doi:10.2174/138161209788453167.

27.    He, X., Gao, Y., Hui, Z., Shen, G., Wang, S., Xie, T., Ye, X. Y., 2020, 4-Hydroxy-3-methylbenzofuran-2-carbohydrazones as novel LSD1 inhibitors. Bioorganic & Medicinal Chemistry Letters, 30(10), 127109.  doi:10.1016/j.bmcl.2020.127109

28.    Tabriz, H. M., Mirzaalizadeh, M., Gooran, S., Niki, F., Jabri, M., 2016, COX-2 expression in renal cell carcinoma and correlations with tumor grade, stage and patient prognosis. Asian Pacific Journal of Cancer Prevention, 17(2), 535-538.  doi:10.7314/APJCP.2016.17.2.535.

29.    Ishibashi, K., Koguchi, T., Matsuoka, K., Onagi, A., Tanji, R., Takinami-Honda, R., Kojima, Y., 2018, Interleukin-6 induces drug resistance in renal cell carcinoma. Fukushima journal of medical science, 64(3), 103-110.  doi:10.5387/fms.2018-15.

30.    Sang, Y. B., Yang, H., Lee, W. S., Lee, S. J., Kim, S. G., Cheon, J., Kim, C., 2022, High serum levels of IL-6 predict poor responses in patients treated with pembrolizumab plus axitinib for advanced renal cell carcinoma. Cancers, 14(23), 5985.  doi:10.3390/cancers14235985.

31.    Chakraborty, S., Balan, M., Sabarwal, A., Choueiri, T. K., Pal, S., 2021, Metabolic reprogramming in renal cancer: events of a metabolic disease. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1876(1), 188559.  doi:10.1016/j.bbcan.2021.188559.

32.    Wang, Z., Jin, D., Zhou, S., Dong, N., Ji, Y., An, P., Luo, J., 2023, Regulatory roles of copper metabolism and cuproptosis in human cancers. Frontiers in oncology, 13, 1123420. doi:10.3389/fonc.2023.1123420.