Synthesis of (3E,5E)-1-benzil-3,5 bis (3 (benziloksi)benziliden)piperidin-4-on curcumin analogues and their potential as breast anticancer agents: Assessment using MTT test and molecular docking
DOI:
https://doi.org/10.24114/jpkim.v16i3.65150Keywords:
Breast cancer, Curcumin analogs, Molecular coding, MTT assay, 3ERTAbstract
Breast cancer is a serious disease that occurs in women and contributes to the highest mortality compared to other types of cancer. This study aims to synthesize curcumin analog compounds ((3E,5E)-1-benzyl-3,5 bis (3 (benzyloxy)benzylidene) piperidin-4-one), test them in vitro against various breast cancer cells (T47D, HER-2, MCF-7, and 4T1) and normal cells (vero cells), and study their molecular docking. Synthesis was carried out by reacting 3-benzyloxybenzaldehyde with N-benzyl-4-piperidone catalyzed by 5% KOH at room temperature; in vitro testing was carried out using the Microculture Tetrazolium Technique Assay method, ADMET analysis with an online database server, and molecular docking studies in Autodoc Vina. The synthesis results obtained yellow solid powder with a yield of 65.85%, characterization with TLC gave black fluorescence (Rf 0.63), melting point 114-116oC, TLC scanner one peak (100%), retention time 0.65 minutes, 1H &13C-NMR analysis showed the molecular formula C40H35NO3, moderate activity against 4T1 breast cancer cells and inactivity on T47D, HER-2, and MCF-7 cancer cells, and did not show cytotoxicity to normal cells (vero cells). ADMET predictions from Lipinski's five rules contained two parameters that did not meet, namely molecular weight and log P value. Molecular docking studies were carried out on estrogen receptor protein (ER)-α (PDB ID: 2ERT), which showed a binding affinity energy of -8.7 kcal/mol and -7.1 kcal/mol of the native ligand. Further research and development is needed on synthetic curcumin analog compounds to increase their activity value against breast cancer by paying attention to Lipinski's five rules to obtain compounds with better potential activity and ADMET.References
Astuti, E., Raharjo, T.J., Boangmanalu, P.M., Putra, I.S.R., Waskitha, S.S.W., Solin, J. 2021. Synthesis, molecular docking, and evaluation of some new curcumin analogs as antimalarial agents. Indonesian Journal of Chemistry 21, 452–461. https://doi.org/10.22146/IJC.57646
Baraya, Y.S.B., Wong, K.K., & Yaacob, N.S. 2016. The immunomodulatory potential of selected bioactive plant-based compounds in breast cancer: A review. Anticancer Agents Med Chem 17. https://doi.org/10.2174/1871520616666160817111242
Barbosa, A.M., Martel, F., 2020. Targeting glucose transporters for breast cancer therapy: The effect of natural and synthetic compounds. Cancers 12, 154. https://doi.org/10.3390/CANCERS12010154
Chunaifah, I., Venilita, R.E., Tjitda, P.J.P., Astuti, E., Wahyuningsih, T.D. 2024. Thiophene-based N-phenyl pyrazolines: synthesis, anticancer activity, molecular docking and ADME study. J Appl Pharm Sci 14, 063–071. https://doi.org/10.7324/JAPS.2024.146832
Dwi Puspitasari, A., Dwi Pranowo, H., Astuti, E., Dwi Wahyuningsih, T. 2020. Design of new chlorochalcone derivatives as potential breast anticancer compound based on QSAR analysis and molecular docking study. CMUJ. Nat. Sci. 2021 20, 2021070–2021071. https://doi.org/10.12982/CMUJNS.2021.070
El-Masry, O.S., Brown, B.L., Dobson, P.R.M. 2019. AMPK activation of apoptotic markers in human breast cancer cell lines with different p53 backgrounds: MCF-7, MDA-MB-231 and T47D Cells. Asian Pac J Cancer Prev 20, 3763. https://doi.org/10.31557/APJCP.2019.20.12.3763
Fabianowska-Majewska, K., Kaufman-Szymczyk, A., Szymanska-Kolba, A., Jakubik, J., Majewski, G., Lubecka, K. 2021. Curcumin from turmeric rhizome: A potential modulator of DNA methylation machinery in breast cancer inhibition. Nutrients 13, 332. https://doi.org/10.3390/NU13020332
Flint, A.L., Hansen, D.W., Brown, L.V.D., Stewart, L.E., Ortiz, E., Panda, S.S. 2022. Modified curcumins as potential drug candidates for breast cancer: An overview. Molecules 27. https://doi.org/10.3390/molecules27248891
Guan, L., Yang, H., Cai, Y., Sun, L., Di, P., Li, W., Liu, G., Tang, Y., 2019. ADMET-score – a comprehensive scoring function for evaluation of chemical drug-likeness. Medchemcomm 10, 148–157. https://doi.org/10.1039/C8MD00472B
Gurning, K., Suratno, S., Astuti, E., Haryadi, W. 2024. Untargeted LC/HRMS Metabolomics Analysis and Anticancer Activity Assay on MCF-7 and A549 Cells from Coleus amboinicus Lour Leaf Extract. IJ Pharmaceutical Research 23. https://doi.org/10.5812/IJPR-143494
Haryadi, W., Gurning, K., Astuti, E. 2024. Molecular target identification of two Coleus amboinicus leaf isolates toward lung cancer using a bioinformatic approach and molecular docking-based assessment. J Appl Pharm Sci 14, 203–210. https://doi.org/10.7324/japs.2024.164753
Haryadi, W., Pranowo, H.D., 2023. Molecular docking and dynamics analysis of halogenated imidazole chalcone as anticancer compounds. Pharmacia 70, 323-329. https://doi.org/10.3897/PHARMACIA.70.E101989
Hong, R., Xu, B. 2022. Breast cancer: an up-to-date review and future perspectives. Cancer Commun 42, 913-936. https://doi.org/10.1002/cac2.12358
Jia, C.Y., Li, J.Y., Hao, G.F., Yang, G.F. 2020. A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discov Today 25, 248–258. https://doi.org/10.1016/J.DRUDIS.2019.10.014
Jordan, V.C. 2007. New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids 72, 829–842. https://doi.org/10.1016/J.STEROIDS.2007.07.009
Lin, H.Y., Han, H.W., Wang, Y.S., He, D.L., Sun, W.X., Feng, L., Wen, Z.L., Yang, M.K., Lu, G.H., Wang, X.M., Qi, J.L., Yang, Y.H. 2020. Shikonin and 4-hydroxytamoxifen synergistically inhibit the proliferation of breast cancer cells through activating apoptosis signaling pathway in vitro and in vivo. Chinese Medicine 15, 1–14. https://doi.org/10.1186/S13020-020-00305-1/FIGURES/7
Mbese, Z., Khwaza, V., Aderibigbe, B.A. 2019a. Curcumin and its derivatives as potential therapeutic agents in prostate, colon and breast cancers. Molecules 24. https://doi.org/10.3390/molecules24234386
Meiyanto, E., Husnaa, U., Kastian, R.F., Putri, H., Larasati, Y.A., Khumaira, A., Pamungkas, D.D.P., Jenie, R.I., Kawaichi, M., Lestari, B., Yokoyama, T., Kato, J.Y. 2021. The target differences of anti-tumorigenesis potential of curcumin and its analogues against HER-2 positive and triple-negative breast cancer cells. Adv Pharm Bull 11, 188–196. https://doi.org/10.34172/apb.2021.020
Nolan, E., Lindeman, G.J., Visvader, J.E. 2023. Deciphering breast cancer: from biology to the clinic. Cell 186, 1708–1728. https://doi.org/10.1016/J.CELL.2023.01.040
Núñez, C., Capelo, J.L., Igrejas, G., Alfonso, A., Botana, L.M., Lodeiro, C. 2016. An overview of the effective combination therapies for the treatment of breast cancer. Biomaterials 97, 34–50. https://doi.org/10.1016/J.BIOMATERIALS.2016.04.027
Praseetha, N.G., Divya, U.K., Nair, S. 2022. Identifying the potential role of curcumin analogues as anti-breast cancer agents; an in silico approach. Egyptian Journal of Medical Human Genetics 23. https://doi.org/10.1186/s43042-022-00312-x
Rashid, M., 2020. Design, synthesis and ADMET prediction of bis-benzimidazole as anticancer agent. Bioorg Chem 96, 103576. https://doi.org/10.1016/J.BIOORG.2020.103576
Sancha, S.A.R., Szemerédi, N., Spengler, G., Ferreira, M.J.U. 2023. Lycorine carbamate derivatives for reversing P-glycoprotein-mediated multidrug resistance in human colon adenocarcinoma cells. Int J Mol Sci 24, 2061. https://doi.org/10.3390/IJMS24032061/S1
Shah, V., Bhaliya, J., Patel, G.M. 2022. In silico docking and ADME study of deketene curcumin derivatives (DKC) as an aromatase inhibitor or antagonist to the estrogen-alpha positive receptor (Erα+): potent application of breast cancer. Struct Chem 33, 571–600. https://doi.org/10.1007/S11224-021-01871-2/FIGURES/12
Siqueira, M.L.S., Andrade, S.M.V., Vieira, J.L.F., Monteiro, M.C. 2021. A preliminary study on the association of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids in patients with breast cancer. Biomedicine & Pharmacotherapy 142, 111972. https://doi.org/10.1016/J.BIOPHA.2021.111972
Sismindari, Sudibyo, R.S., Astuti, E. 2004. Cytotoxic effects of protein fraction isolated from Curcuma mangga Val rhizomes and containing ribosome-inactivating proteins on cancer cell-lines and normal cell. Indonesian Journal of Chemistry 4, 206–211.
Smolarz, B., Zadrożna Nowak, A., Romanowicz, H. 2022. Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature). Cancers 14, 2569. https://doi.org/10.3390/CANCERS14102569
Song, F., Huo, X., Guo, Z. 2021. Anti-breast cancer potential of natural and synthetic coumarin derivatives. Curr Top Med Chem 21, 1692–1709. https://doi.org/10.2174/1568026621666210303145430/CITE/REFWORKS
Song, X., Dai, M.Z., Luo, Y. 2019. Molecular targets of curcumin in breast cancer (Review). Molecular Medicine report 23–29. https://doi.org/10.3892/mmr.2018.9665
Subramanian, A., Manigandan, A., P.R., S., Sethuraman, S. 2015. Development of nanotheranostics against metastatic breast cancer — A focus on the biology & mechanistic approaches. Biotechnol Adv 33, 1897–1911. https://doi.org/10.1016/J.BIOTECHADV.2015.10.002
Sun, D., Chen, G., Dellinger, R.W., Duncan, K., Fang, J.L., Lazarus, P. 2006. Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants. Breast Cancer Research 8, 1–11. https://doi.org/10.1186/BCR1539/TABLES/1
Trayes, K., Cokenakes, S. 2021. Breast cancer treatment. Am Fam Physician 104, 171–178.
Wang, X., Yang, Y., An, Y., Fang, G. 2019. The mechanism of anticancer action and potential clinical use of kaempferol in the treatment of breast cancer. Biomedicine & Pharmacotherapy 117, 109086. https://doi.org/10.1016/J.BIOPHA.2019.109086
Widiandani, T., Tandian, T., Zufar, B.D., Suryadi, A., Purwanto, B.T., Hardjono, S., Siswandono, S. 2023. In vitro study of pinostrobin propionate and pinostrobin butyrate: Cytotoxic activity against breast cancer cell T47D and its selectivity index. J Public Health Afr 14, 2516. https://doi.org/10.4081/JPHIA.2023.2516
Yang, L., Yong, L., Zhu, X., Feng, Y., Fu, Y., Kong, D., Lu, W., Zhou, T-Y. 2020. Disease progression model of 4T1 metastatic breast cancer. J Pharmacokinet Pharmacodyn 47, 105–116. https://doi.org/10.1007/S10928-020-09673-5/FIGURES/5
Zulkipli, N.N., Rahman, S.A., Taib, W.R.W., Razali, R.M., Ismail, I., Ahmad, W.A.N.W., Daud, C.K.D.C.K. 2024. The cytotoxicity effect and identification of bioactive compounds of Prismatomeris glabra crude leaf extracts against breast cancer cells. Beni Suef Univ J Basic Appl Sci 13, 1–18. https://doi.org/10.1186/S43088-024-00490-0/FIGURES/7
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