3,4,5-Trimethoxychalcones Tubulin Inhibitors with a Stable Colchicine Binding Site as Potential Anticancer Agents

Maadh Jumaah; Tutik Dwi Wahyuningsih; Melati Khairuddean

doi:10.22146/ijc.72790

3,4,5-Trimethoxychalcones Tubulin Inhibitors with a Stable Colchicine Binding Site as Potential Anticancer Agents

https://doi.org/10.22146/ijc.72790

Maadh Jumaah⁽¹⁾, Tutik Dwi Wahyuningsih⁽²⁾, Melati Khairuddean^(3*)

(1) School of Chemical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(3) School of Chemical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
(*) Corresponding Author

Abstract

The development of microtubule perturbing drugs is one of the most promising anticancer therapeutic methods. Unfortunately, limitation such as drug resistance, adverse side effects, complex formulations and synthesis, and limited bioavailability of these microtubule perturbing drugs has aroused the search for a new molecule of the tubulin system. Different substituents of chalcone were designed, synthesized, and determined for inhibition of tubulin assembly and toxicity in human cancer cell lines based on conventional colchicine site ligands and a computer model of the colchicine binding site on tubulin. A molecular docking study indicated that the chalcone scaffold could fit the colchicine site on tubulin in a similar orientation to the natural product. The 3,4,5-trimethoxyphenyl ring, which occupies the same sub-cavity as the equivalent molecule in colchicine, appeared to benefit the ligand of α,β-tubulin interaction. Several 3,4,5-trimethoxychalcone compounds demonstrated improved cytotoxicity against MCF-7 cells and inhibited tubulin assembly in vitro as potently as colchicine. The most active chalcone 1 with the IC₅₀ of 6.18 ± 0.69 μM prevented the proliferation of human cell lines at micromolar concentrations, causing microtubule destabilization and mitotic arrest in humans inhibiting breast cancer cells.

Keywords

microtubules; 3,4,5-trimethoxychalcone; docking study; colchicine; MCF-7 cells

Full Text:

Full Text PDF

References

[1] Ilan, Y., 2019, Microtubules: From understanding their dynamics to using them as potential therapeutic target, J. Cell. Physiol., 234 (6), 7923–7937.

[2] Downing, K.H., and Nogales, E., 1998, Tubulin structure: Insights into microtubule properties and functions, Curr. Opin. Struct. Biol., 8 (6), 785–791.

[3] Dumontet, C., and Jordan, M.A., 2010, Microtubule-binding agents: A dynamic field of cancer therapeutics, Nat. Rev. Drug Discovery, 9 (10), 790–803.

[4] Arnst, K.E., Banerjee, S., Chen, H., Deng, S., Hwang, D.J., Li, W., and Miller, D.D., 2019, Current advances of tubulin inhibitors as dual-acting small molecules for cancer therapy, Med. Res. Rev., 39 (4), 1398–1426.

[5] Čermák, V., Dostál, V., Jelínek, M., Libusová, L., Kovář, J., Rösel, D., and Brábek, J., 2020, Microtubule-targeting agents and their impact on cancer treatment, Eur. J. Cell Biol., 99 (4), 151075.

[6] Steinmetz, M.O., and Prota, A.E., 2018, Microtubule-targeting agents: Strategies to hijack the cytoskeleton, Trends Cell Biol., 28 (10), 776–792.

[7] Karahalil, B., Yardım-Akaydin, S., and Nacak Baytas, S., 2019, An overview of microtubule targeting agents for cancer therapy, Arh. Hig. Rada Toksikol., 70 (3), 160–172.

[8] Dyrager, C., Wickström, M., Fridén-Saxin, M., Friberg, A., Dahlén, K., Wallén, E.A.A., Gullbo, J., Grøtli, M., and Luthman, K., 2011, Inhibitors and promoters of tubulin polymerization: Synthesis and biological evaluation of chalcones and related dienones as potential anticancer agents, Bioorg. Med. Chem., 19 (8), 2659–2665.

[9] Ouyang, Y., Li, J., Chen, X., Fu, X., Sun, S., and Wu, Q., 2021, Chalcone derivatives: Role in anticancer therapy, Biomolecules, 11 (6), 894.

[10] Liu, W., He, M., Li, Y., Peng, Z., and Wang, G., 2022, A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors, J. Enzyme Inhib. Med. Chem., 37 (1), 9–38.

[11] Jumaah, M., Khairuddean, M., Owaid, S.J., Zakaria, N., Mohd Arshad, N., Nagoor, N.H., and Mohamad Taib, M.N.A., 2022, Design, synthesis, characterization and cytotoxic activity of new ortho-hydroxy and indole-chalcone derivatives against breast cancer cells (MCF-7), Med. Chem. Res., 31 (3), 517–532.

[12] Peng, F., Meng, C.W., Zhou, Q.M., Chen, J.P., and Xiong, L., 2016, Cytotoxic evaluation against breast cancer cells of isoliquiritigenin analogues from Spatholobus suberectus and their synthetic derivatives, J. Nat. Prod., 79 (1), 248–251.

[13] Karthikeyan, C., Narayana Moorthy, N.S.H., Ramasamy, S., Vanam, U., Manivannan, E., Karunagaran, D., and Trivedi, P., 2015, Advances in chalcones with anticancer activities, Recent Pat. Anti-Cancer Drug Discovery, 10 (1), 97–115.

[14] Shin, S.Y., Kim, J.H., Yoon, H., Choi, Y.K., Koh, D., Lim, Y., and Lee, Y.H., 2013, Novel antimitotic activity of 2-hydroxy-4-methoxy-2′,3′-benzochalcone (HymnPro) through the inhibition of tubulin polymerization, J. Agric. Food Chem., 61 (51), 12588–12597.

[15] McLoughlin, E.C., and O’Boyle, N.M., 2020, Colchicine-binding site inhibitors from chemistry to clinic: A review, Pharmaceuticals, 13 (1), 8.

[16] Kumbhar, B.V., Borogaon, A., Panda, D., and Kunwar, A., 2016, Exploring the origin of differential binding affinities of human tubulin isotypes αβII, αβIII and αβIV for DAMA-colchicine using homology modelling, molecular docking and molecular dynamics simulations, PLoS One, 11 (5), e0156048.

[17] Salum, L.B., Mascarello, A., Canevarolo, R.R., Altei, W.F., Laranjeira, A.B., Neuenfeldt, P.D., Stumpf, T.R., Chiaradia-Delatorre, L.D., Vollmer, L.L., Daghestani, H.N., de Souza Melo, C.P., Silveira, A.B., Leal, P.C., Frederico, M.J.S., do Nascimento, L.F., Santos, A.R.S., Andricopulo, A.D., Day, B.W., Yunes, R.A., Vogt, A., Yunes, J.A., and Nunes, R.J., 2015, N-(1′-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia, Eur. J. Med. Chem., 96, 504–518.

[18] Dong, M., Liu, F., Zhou, H., Zhai, S., and Yan, B., 2016, Novel natural product-and privileged scaffold-based tubulin inhibitors targeting the colchicine binding site, Molecules, 21 (10), 1375.

[19] Lipinski, C.A., Lombardo, F., Dominy, B.W., and Feeney, P.J., 2001, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Delivery Rev., 46 (1-3), 3–26.

[20] Ramírez, D., and Caballero, J., 2018, Is it reliable to take the molecular docking top scoring position as the best solution without considering available structural data?, Molecules, 23 (5), 1038.

[21] Torres, P.H.M., Sodero, A.C.R., Jofily, P., and Silva-Jr, F.P., 2019, Key topics in molecular docking for drug design, Int. J. Mol. Sci., 20 (18), 4574.

DOI: https://doi.org/10.22146/ijc.72790