Nguyen Hai Dang , Nguyen Cuong Quoc , Phan Nguyet Tho , Duong Quoc Viet , Nguyen Thien Huong , Le Dang Quang , Bui Thi Buu Hue , Nguyen Trong Tuan and Tran Quang De *

* Corresponding author (tqde@ctu.edu.vn)

Abstract

Histone deacetylase (HDAC) is a significant target in cancer therapy. In this work, the dataset of 32 metal-chelating compounds was designed based on the chalcone-sulfonamide scaffold. Molecular docking was conducted on HDAC class I family members. The results revealed robust interactions of these compounds with key amino acids at the active site, all displaying binding energies lower than -15 kJ/mol. Notably, derivative 20, a 2'-hydroxychalcone-sulfonamide compound bearing a meta-NO2 substituent, exhibited the most promising efficacy across all selected HDAC enzymes. This compound holds great potential for synthetic and biological evaluations in the future.

Keywords: Cancer, chalcone, docking, HAT, HDAC

Tóm tắt

HDAC là mục tiêu quan trọng trong liệu pháp điều trị ung thư. Trong nghiên cứu này, bộ dữ liệu bao gồm 32 hợp chất có khả năng chelate với kim loại đã được thiết kế dựa trên khung sườn chalcone-sulfonamide. Docking phân tử đã được thực hiện trên các loại HDAC nhóm I. Kết quả cho thấy các hợp chất đều thể hiện các tương tác mạnh mẽ với các amino acid tại vị trí hoạt động. Năng lượng liên kết đều thấp hơn -15 kJ/mol. Đặc biệt, dẫn xuất 20 là hợp chất 2‘-hydroxychalcone-sulfonamide với nhóm thế meta-NO2 cho hiệu quả tốt nhất với cả ba enzyme HDAC. Đây được xem là ứng viên tiềm năng cho các nghiên cứu tổng hợp và đánh giá hoạt tính sinh học trong tương lai.

Từ khóa: Chalcone, docking, HAT, HDAC, ung thư

Article Details

References

Bello, E. D., Noce, B., Fioravanti, R., & Mai, A. (2022). Current HDAC Inhibitors in Clinical Trials. CHIMIA, 76(5), Article 5. https://doi.org/10.2533/chimia.2022.448

Bertrand, P. (2010). Inside HDAC with HDAC inhibitors. European Journal of Medicinal Chemistry, 45(6), 2095–2116. https://doi.org/10.1016/j.ejmech.2010.02.030

Bolden, J. E., Peart, M. J., & Johnstone, R. W. (2006). Anticancer activities of histone deacetylase inhibitors. Nature Reviews Drug Discovery, 5(9), Article 9. https://doi.org/10.1038/nrd2133

Géraldy, M., Morgen, M., Sehr, P., Steimbach, R. R., Moi, D., Ridinger, J., Oehme, I., Witt, O., Malz, M., Nogueira, M. S., Koch, O., Gunkel, N., & Miller, A. K. (2019). Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated. Journal of Medicinal Chemistry, 62(9), 4426–4443. https://doi.org/10.1021/acs.jmedchem.8b01936

Ibrahim, H. S., Abdelsalam, M., Zeyn, Y., Zessin, M., Mustafa, A.-H. M., Fischer, M. A., Zeyen, P., Sun, P., Bülbül, E. F., Vecchio, A., Erdmann, F., Schmidt, M., Robaa, D., Barinka, C., Romier, C., Schutkowski, M., Krämer, O. H., & Sippl, W. (2022). Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity. International Journal of Molecular Sciences, 23(1), Article 1. https://doi.org/10.3390/ijms23010369

Johnstone, R. W. (2002). Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer. Nature Reviews Drug Discovery, 1(4), Article 4.
https://doi.org/10.1038/nrd772

Kumar, N., Tomar, R., Pandey, A., Tomar, V., Singh, V. K., & Chandra, R. (2018). Preclinical evaluation and molecular docking of 1,3-benzodioxole propargyl ether derivatives as novel inhibitor for combating the histone deacetylase enzyme in cancer. Artificial Cells, Nanomedicine, and Biotechnology, 46(6), 1288–1299. https://doi.org/10.1080/21691401.2017.1369423

Li, Y., & Seto, E. (2016). HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harbor Perspectives in Medicine, 6(10), a026831. https://doi.org/10.1101/cshperspect.a026831

Lombardi, P. M., Cole, K. E., Dowling, D. P., & Christianson, D. W. (2011). Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes. Current Opinion in Structural Biology, 21(6), 735–743. https://doi.org/10.1016/j.sbi.2011.08.004

Mai, A., Massa, S., Valente, S., Simeoni, S., Ragno, R., Bottoni, P., Scatena, R., & Brosch, G. (2006). Aroyl-Pyrrolyl Hydroxyamides: Influence of Pyrrole C4-Phenylacetyl Substitution on Histone Deacetylase Inhibition. ChemMedChem, 1(2), 225–237. https://doi.org/10.1002/cmdc.200500015

Nam, N. H., Huong, T. L., Dung, D. T. M., Dung, P. T. P., Oanh, D. T. K., Park, S. H., Kim, K., Han, B. W., Yun, J., Kang, J. S., Kim, Y., & Han, S. B. (2014). Synthesis, bioevaluation and docking study of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents. Journal of Enzyme Inhibition and Medicinal Chemistry, 29(5), 611–618. https://doi.org/10.3109/14756366.2013.832238

Orlikova, B., Schnekenburger, M., Zloh, M., Golais, F., Diederich, M., & Tasdemir, D. (2012). Natural chalcones as dual inhibitors of HDACs and NF-κB. Oncology Reports, 28(3), 797–805. https://doi.org/10.3892/or.2012.1870

Phuong, N. H., De, T. Q., Quoc, N. C., Phuong, H. T., Binh, T. D., Thao, H. N., Hue, B. B. T., Tuan, T. N., Dang, Q. L., Thanh, N. Q. C., Ky, N. V., Quan, P. M., & Yang, S. G. (2022). Anti-multiple myeloma potential of resynthesized belinostat derivatives: An experimental study on cytotoxic activity, drug combination, and docking studies. RSC Advances, 12(34), 22108–22118. https://doi.org/10.1039/D2RA01969H

Rettig, I., Koeneke, E., Trippel, F., Mueller, W. C., Burhenne, J., Kopp-Schneider, A., Fabian, J., Schober, A., Fernekorn, U., von Deimling, A., Deubzer, H. E., Milde, T., Witt, O., & Oehme, I. (2015). Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. Cell Death & Disease, 6(2), Article 2. https://doi.org/10.1038/cddis.2015.24

Ropero, S., & Esteller, M. (2007). The role of histone deacetylases (HDACs) in human cancer. Molecular Oncology, 1(1), 19–25. https://doi.org/10.1016/j.molonc.2007.01.001

Scafuri, B., Bontempo, P., Altucci, L., De Masi, L., & Facchiano, A. (2020). Molecular Docking Simulations on Histone Deacetylases (HDAC)-1 and -2 to Investigate the Flavone Binding. Biomedicines, 8(12), Article 12. https://doi.org/10.3390/biomedicines8120568

Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., Chakravarty, P., Paolini, C., De Francesco, R., Gallinari, P., Steinkühler, C., & Di Marco, S. (2004). Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences, 101(42), 15064–15069. https://doi.org/10.1073/pnas.0404603101

Weichert, W., Röske, A., Gekeler, V., Beckers, T., Stephan, C., Jung, K., Fritzsche, F. R., Niesporek, S., Denkert, C., Dietel, M., & Kristiansen, G. (2008). Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. British Journal of Cancer, 98(3), Article 3. https://doi.org/10.1038/sj.bjc.6604199

Zhou, J., Li, M., Chen, N., Wang, S., Luo, H.-B., Zhang, Y., & Wu, R. (2015). Computational Design of a Time-Dependent Histone Deacetylase 2 Selective Inhibitor. ACS Chemical Biology, 10(3), 687–692. https://doi.org/10.1021/cb500767c