Synthesis, Cytotoxicity Evaluation and Molecular Docking Studies of Xanthyl-Cinnamate Derivatives as Potential Anticancer Agents

Muthia Rahayu Iresha; Jumina Jumina; Harno Dwi Pranowo; Eti Nurwening Sholikhah; Faris Hermawan

doi:10.22146/ijc.76164

Synthesis, Cytotoxicity Evaluation and Molecular Docking Studies of Xanthyl-Cinnamate Derivatives as Potential Anticancer Agents

https://doi.org/10.22146/ijc.76164

Muthia Rahayu Iresha⁽¹⁾, Jumina Jumina^(2*), Harno Dwi Pranowo⁽³⁾, Eti Nurwening Sholikhah⁽⁴⁾, Faris Hermawan⁽⁵⁾

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia; Austrian-Indonesian Centre (AIC) for Computational Chemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(3) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia; Austrian-Indonesian Centre (AIC) for Computational Chemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(4) Department of Pharmacology and Therapeutics, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia; Austrian-Indonesian Centre (AIC) for Computational Chemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(*) Corresponding Author

Abstract

A new series of xanthyl-cinnamate hybrid compounds (4a-d) have been synthesized and screened through in vitro assay against four human cancer cell lines, i.e., HeLa, T47D, A549, and WiDr. The results revealed that xanthone hybridization with cinnamic acid increases the selectivity of the compounds with SI values of 2.75–209.03 compared to its parent oxygenated-xanthone. Compound 1,3-dihydroxyxanthen-6-yl cinnamate (4c) showed high cytotoxic activity against WiDr cell lines with an IC₅₀ value of 39.57 µM. Molecular docking studies revealed the possible binding modes of all hybrid compounds with EGFR protein. A complex of 3,6-dihydroxyxanthen-1-yl cinnamate (4d)-EGFR, as the best binding model, exhibited higher predicted EGFR inhibitory activity than erlotinib and oxygenated-xanthone with a ΔG and Ki value of -35.02 kJ/mol and 0.74 µM, respectively. Compounds 4c and 4d were chosen as the most potent derivates from the study.

Keywords

xanthyl-cinnamate; xanthone; cinnamic acid; anticancer; hybrid molecule

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References

[1] Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., and Bray, F., 2021, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 71 (3), 209–249.

[2] Schirrmacher, V., 2019, From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment, Int. J. Oncol., 54 (2), 407–419.

[3] Zhang, C., Yu, G., and Shen, Y., 2018, The naturally occurring xanthone α-mangostin induces ROS-mediated cytotoxicity in non-small scale lung cancer cells, Saudi J. Biol. Sci., 25 (6), 1090–1095.

[4] Kaewpiboon, C., Boonnak, N., Yawut, N., Kaowinn, S., and Chung, Y.H., 2019, Caged-xanthone from Cratoxylum formosum ssp. pruniflorum inhibits malignant cancer phenotypes in multidrug-resistant human A549 lung cancer cells through down-regulation of NF-κB, Bioorg. Med. Chem., 27 (12), 2368–2375.

[5] Wu, J., Dai, J., Zhang, Y., Wang, J., Huang, L., Ding, H., Li, T., Zhang, Y., Mao, J., and Yu, S., 2019, Synthesis of novel xanthone analogues and their growth inhibitory activity against human lung cancer A549 cells, Drug Des., Dev. Ther., 13, 4239–4246.

[6] Pinto, M.M.M., Palmeira, A., Fernandes, C., Resende, D.I.S.P., Sousa, E., Cidade, H., Tiritan, M.E., Correia-da-Silva, M., and Cravo, S., 2021, From natural products to new synthetic small molecules: A journey through the world of xanthones, Molecules, 26 (2), 431.

[7] Fatmasari, N., Kurniawan, Y.S., Jumina, J., Anwar, C., Priastomo, Y., Pranowo, H.D., Zulkarnain, A.K., and Sholikhah, E.N., 2022, Synthesis and in vitro assay of hydroxyxanthones as antioxidant and anticancer agents, Sci. Rep., 12 (1), 1535.

[8] Yuanita, E., Pranowo, H.D., Mustofa, M., Swasono, R.T., Syahri, J., and Jumina, J., 2019, Synthesis, characterization and molecular docking of chloro-substituted hydroxyxanthone derivatives, Chem. J. Mold., 14 (1), 68–76.

[9] Takahashi, T., and Miyazawa, M., 2010, Tyrosinase inhibitory activities of cinnamic acid analogues, Pharmazie, 65, 913–918.

[10] de Oliveira Niero, E.L., and Machado-Santelli, G.M., 2013, Cinnamic acid induces apoptotic cell death and cytoskeleton disruption in human melanoma cells, J. Exp. Clin. Cancer Res., 32 (1), 31.

[11] Keawsa-ard, S., Natakankitkul, S., Liawruangrath, S., Teerawutkulrag, A., Trisuwan, K., Charoenying, P., Pyne, S.G., and Liawruangrath, B., 2012, Anticancer and antibacterial activities of the isolated compounds from Solanum spirale Roxb. leaves, Chiang Mai J. Sci., 39 (3), 445–454.

[12] do Vale, J.A., Rodrigues, M.P., Lima, A.M.A., Santiago, S.S., Lima, G.D.A., Almeida, A.A., de Oliveira, L.L., Bressan, G.C., Teixeira, R.R., and Machado-Neves, M., 2022, Synthesis of cinnamic acid ester derivatives with antiproliferative and antimetastatic activities on murine melanoma cells, Biomed. Pharmacother., 148, 112689.

[13] Ruwizhi, N., and Aderibigbe, B.A., 2020, Cinnamic acid derivatives and their biological efficacy, Int. J. Mol. Sci., 21 (16), 5712.

[14] Ge, Y.X., Wang, Y.H., Zhang, J., Yu, Z.P., Mu, X., Song, J.L., Wang, Y.Y., Yang, F., Meng, N., Jiang, C.S., and Zhang, H., 2019, New cinnamic acid-pregenolone hybrids as potential antiproliferative agents: Design, synthesis and biological evaluation, Steroids, 152, 108499.

[15] Ruan, B.F., Ge, W.W., Cheng, H.J., Xu, H.J., Li, Q.S., and Liu, X.H., 2017, Resveratrol-based cinnamic ester hybrids: Synthesis, characterization, and anti-inflammatory activity, J. Enzyme Inhib. Med. Chem., 32 (1), 1282–1290.

[16] Deng, Z., Li, C., Luo, D., Teng, P., Guo, Z., Tu, X., Zou, K., and Gong, D., 2017, A new cinnamic acid derivative from plant-derived endophytic fungus Pyronema sp., Nat. Prod. Res., 31 (20), 2413–2419.

[17] Xu, C.C., Deng, T., Fan, M.L., Lv, W.B., Liu, J.H., and Yu, B.Y., 2016, Synthesis and in vitro antitumor evaluation of dihydroartemisinin-cinnamic acid ester derivatives, Eur. J. Med. Chem., 107, 192–203.

[18] Shang, H., Li, L., Ma, L., Tian, Y., Jia, H., Zhang, T., Yu, M., and Zou, Z., 2020, Design and synthesis of molecular hybrids of sophora alkaloids and cinnamic acids as potential antitumor agents, Molecules, 25 (5), 1168.

[19] Das, A., Shaikh, M.M., and Jana, S., 2014, Design, synthesis, and in vitro antibacterial screening of some novel 3-pentyloxy-1-hydroxyxanthone derivatives, Med. Chem. Res., 23 (1), 436–444.

[20] Iresha, M.R., Jumina, J., and Pranowo, H.D., 2020, Molecular docking study of xanthyl chalcone derivatives as potential inhibitor agents against KIT tyrosine kinase and KIT kinase domain mutant D816H, J. Appl. Pharm. Sci., 10 (11), 18–26.

[21] Miladiyah, I., Jumina, J., Haryana, S.M., and Mustofa, M., 2018, Biological activity, quantitative structure-activity relationship analysis, and molecular docking of xanthone derivatives as anticancer drugs, Drug Des., Dev. Ther., 12, 149–158.

[22] Badisa, R.B., Darling-Reed, S.F., Joseph, P., Cooperwood, J.S., Latinwo, L.M., and Goodman, C.B., 2009, Selective cytotoxic activities of two novel synthetic drugs on human breast carcinoma MCF-7 cells, Anticancer Res., 29 (8), 2993–2996.

[23] Mencher, S.K., and Wang, L.G., 2005, Promiscuous drugs compared to selective drugs (promiscuity can be a virtue), BMC Clin. Pharmacol., 5 (1), 3.

[24] Wong, C.C., Cheng, K.W., and Rigas, B., 2012, Preclinical predictors of anticancer drug efficacy: Critical assessment with emphasis on whether nanomolar potency should be required of candidate agents, J. Pharmacol. Exp. Ther., 341 (3), 572–578.

[25] Jung, K.H., Lee, E.J., Park, J.W., Lee, J.H., Moon, S.H., Cho, Y.S., and Lee, K.H., 2019, EGF receptor stimulation shifts breast cancer cell glucose metabolism toward glycolytic flux through PI3 kinase signaling, PLoS One, 14 (9), e0221294.

[26] McGaffin, K.R., Acktinson, L.E., and Chrysogelos, S.A., 2004, Growth and EGFR regulation in breast cancer cells by vitamin D and retinoid compounds, Breast Cancer Res. Treat., 86 (1), 55–73.

[27] Qian, Y., Qiu, M., Wu, Q., Tian, Y., Zhang, Y., Gu, N., Li, S., Xu, L., and Yin, R., 2014, Enhanced cytotoxic activity of cetuximab in EGFR-positive lung cancer by conjugating with gold nanoparticles, Sci. Rep., 4 (1), 7490.

[28] Shigeta, K., Hayashida, T., Hoshino, Y., Okabayashi, K., Endo, T., Ishii, Y., Hasegawa, H., and Kitagawa, Y., 2013, Expression of epidermal growth factor receptor detected by cetuximab indicates its efficacy to inhibit in vitro and in vivo proliferation of colorectal cancer cells, PLoS One, 8 (6), e66302.

[29] Stamos, J., Sliwkowski, M.X., and Eigenbrot, C., 2002, Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor, J. Biol. Chem., 277 (48), 46265–46272.

DOI: https://doi.org/10.22146/ijc.76164