Medicinal Chemistry Research

, Volume 28, Issue 10, pp 1773–1782 | Cite as

New histone deacetylase inhibitors and anticancer agents from Curcuma longa

  • Pakit Kumboonma
  • Thanaset Senawong
  • Somprasong Saenglee
  • Gulsiri Senawong
  • La-or Somsakeesit
  • Chavi Yenjai
  • Chanokbhorn PhaosiriEmail author
Original Research


The aims of this study were to explore histone deacetylase inhibitory and antioxidant activities of curcuminoids as well as derivatives of curcumin. Curcumin (6), demethoxycurcumin (7), dihydrocurcumin (8), bisdemethoxycurcumin (9), and hydroxycurcumin (10) were isolated and tested against histone deacetylases in HeLa nuclear extract. Hydroxycurcumin (10) showed the best inhibition among the isolated compounds. Some curcumin derivatives were also prepared and tested. The potential derivatives were tested on five cancer cell lines. All compounds exhibited slightly weaker antiproliferative activities against cancer cells and less toxic to non-cancer cells than curcumin (6). The least toxic derivative (17) exhibited the best antiproliferative activity against human cervical cancer cell lines (HeLa) with the IC50 value of 4.69 ± 0.14 μM. The most active histone deacetylase inhibitor (19) showed the highest potency against human colon cancer cell lines (HCT116) and the selective binding to HDAC4 based on molecular docking experiments. Most derivatives possessed antioxidant activities superior to curcumin. The results suggested potential candidates for anticancer agents.


Turmeric Curcumin HeLa cell Anticancer Molecular docking 



Khon Kaen University is gratefully acknowledged for the financial support of this work (Grant Number 6200014002). We also would like to thank Mr. Kittisak Poopasith for the excellent NMR data. We are thankful to the Postdoctoral Training Program, Graduate School, Khon Kaen University for providing a fellowship to Dr. Somprasong Saenglee. A graduate fellowship given to Pakit Kumboonma and La-or Somsakeesit is supported by Rajamangala University of Technology Isan (RMUTI).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2414_MOESM1_ESM.pdf (1.5 mb)
Supplementary data 1.
44_2019_2414_MOESM2_ESM.pdf (142 kb)
Supplementary data 2.
44_2019_2414_MOESM3_ESM.pdf (332 kb)
Supplementary data 3.


  1. Ahsan MJ, Choudhary K, Jadav SS, Yasmin S, Ansari MY, Sreennivasulu R (2015) Synthesis, antiproliferative activity, and molecular docking studies of curcumin analogues bearing pyrozole ring. Med Chem Res 24:4166–4180CrossRefGoogle Scholar
  2. Anand P, Thomas SG, Kunnumakkara AB, Sundaram C, Harikumar KB, Sung B et al. (2008) Biological activities of curcumin and its analogues (congeners) made by man and mother nature. Biochem Pharm 76:1590–1611CrossRefGoogle Scholar
  3. Asgar MA, Senawong G, Sripa B, Senawong T (2016) Synergistic anticancer effects of cisplatin and histone deacetylase inhibitors (SAHA and TSA) on cholangiocarcinoma cell lines. Int J Oncol 48:409–420CrossRefGoogle Scholar
  4. Assaashari M, Farhoosh R, Sharif A (2014) Antioxidnt activity of gallic acid and methyl gallate in triacylglycerols of kika fish oil and its oil-in-water emulsion. Food Chem 159:439–444CrossRefGoogle Scholar
  5. Banerjee S, Adhikari N, Amin SA, Jha T (2019) Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: an overview. Eur J Med Chem 164:214–240CrossRefGoogle Scholar
  6. Berber A, Zengin G, Aktumsek A, Sanda MA, Uysal T (2014) Antioxidant capacity and fatty acid composition of different parts of Adenocarpus complicates (Fabaceae) from Turkey. Rev Biol Trop 62:337–346CrossRefGoogle Scholar
  7. Bertrand P (2010) Inside HDAC with HDAC inhibitors. Eur J Med Chem 45:2095–2116CrossRefGoogle Scholar
  8. Bürli RW, Luckhurst CA, Aziz O, Matthews KL, Yates D, Lyons KA et al. (2013) Design, synthesis, and biological evaluation of potent and selective class Iia histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington’s disease. J Med Chem 56:9934–9954CrossRefGoogle Scholar
  9. Chan MMY, Ho CT, Huang HI (1995) Effects of three dietary phytochemicals from tea, rosemary and turmeric on inflammation-induced nitrite production. Cancer Lett 96:23–29CrossRefGoogle Scholar
  10. Changtam C, Hongmanee P, Suksamrarn A (2010) Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial. Eur J Med Chem 45:4446–4457CrossRefGoogle Scholar
  11. Gopalan B, Ponpandian T, Kachhadia V, Bharathimohan K, Vignesh R, Sivasudar V, Narayanan S, Mandar B, Praveen R, Saranya N, Rajagopal S, Rajagopal S (2013) Discovery of adamantane based highly potent HDAC inhibitors. Bioorg Med Chem Lett 23:2532–2537CrossRefGoogle Scholar
  12. Hahnen E, Hauke J, Trankle C, Eyupoglu IY, Wirth B, Blumcke I (2008) Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin Invest Drugs 17:169–184CrossRefGoogle Scholar
  13. Hu J, An B, Pan T, Li Z, Huang L, Li X (2018) Design, synthesis, and biological evaluation of histone deacetylase inhibitors possessing glutathione peroxidase-like and antioxidant activities against Alzheimer’s disease. Bioorg Med Chem 26:5718–5729CrossRefGoogle Scholar
  14. Inano H, Onoda M, Inafugu N, Kubota M, Kamada Y, Osawa T, Kobayashi H, Wakabayashi K (2000) Potent preventive action of curcumin on radiation-induced initiation of mammary tumorigenesis in rats. Carcinogenesis 21:1835–1841CrossRefGoogle Scholar
  15. Jha NS, Mishra S, Jha SK, Surolia A (2015) Antioxidant activity and electrochemical elucidation of the enigmatic redox behavior of curcumin and its structurally modified analogues. Electro Acta 151:574–583CrossRefGoogle Scholar
  16. Jordan BC, Kumar B, Thilagavathi R, Yadhav A, Kumar P, Selvam C (2018) Synthesis, evaluation of cytotoxic properties of promising curcumin analogues and investigation of possible molecular mechanisms. Chem Biol Drug Des 91:332–337CrossRefGoogle Scholar
  17. Khalil MI, AL-Zahem AM, Qunaibit MM (2014) Synthesis, characterization, and antitumor activity of binuclear curcumin-metal (II) hydroxo complexes. Med Chem Res 23:1683–1689CrossRefGoogle Scholar
  18. Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG (2007) Focus on acetylation: the role of histone deacetylase inhibitors in cancer therapy and beyond. Expert Opin Invest Drugs 16:569–571CrossRefGoogle Scholar
  19. Kumboonma P, Senawong T, Saenglee S, Yenjai C, Phaosiri C (2017) Identificaton of phenolic compounds from Zingiber offinale and their derivatives as histone deacetylase inhibitors and antioxidants. Med Chem Res 26:650–661CrossRefGoogle Scholar
  20. Kumnerdkhonkaen P, Saenglee S, Asgar MA, Senawong G, Khongsukwiwat K, Senawong T (2018) Antiproliferative activities and phenolic acid content of water and ethanolic extracts of the powdered formula of Houttuynia cordata Thunb. fermented broth and Phyllanthus emblica Linn. fruit. BMC Complement Altern Med 18:130–132CrossRefGoogle Scholar
  21. Manal M, Chandrasekar MJN, Priya JG, Nanjan MJ (2016) Inhibitors of histone deacetylase as antitumor agents: a critical review. Bioorg Chem 67:18–42CrossRefGoogle Scholar
  22. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12:1247–1252CrossRefGoogle Scholar
  23. Mazumder A, Raghavan K, Weinstein L, Kohn KW, Pommier Y (1995) Inhibition of human immunodeficiency virus type-1 integrase by curcumin. Biochem Pharm 49:1165–1170CrossRefGoogle Scholar
  24. Micelli C, Rastelli G (2015) Histone deacetylases: structural determinants of inhibitor selectivity. Drug Discov Today 20:718–735CrossRefGoogle Scholar
  25. Miller TA, Witter DJ, Belvedere S (2003) Histone deacetylase inhibitors. J Med Chem 46:5097–5116CrossRefGoogle Scholar
  26. Mishra S, Karmodiya K, Surolia N, Surolia A (2008) Synthesis and exploration of novel curcumin analogues as anti-malarial agents. Bioorg Med Chem 16:2894–2902CrossRefGoogle Scholar
  27. Noh H, Oh EY, Seo JY, Yu MR, Kim YO, Ha H (2009) Histone deacetylase-2 is a key regulator of diabetes and transforming growth factor-β1-induced renal injury. Am J Physiol Ren Physiol 207:729–739CrossRefGoogle Scholar
  28. Oktay M, Gulcin I, Kufrevioglu OI (2003) Determination of in vitro antioxidant activity of fennel (Foeniculum vulgare) seed extracts. Leb Wiss Technol 36:263–271CrossRefGoogle Scholar
  29. Ontoria JM, Altamura S, Marco AD, Ferrigno F, Laufer R, Muraglia E, Palumbi MC, Rowley M, Scarpelli R, Fademrecht CS, Serafini S, Steinkühler C, Jones P (2009) Identification of novel, selective, and stable inhibitors of class II histone deacetylases. Validation studies of the inhibition of the enzymatic activity of HDAC4 by small molecules as a novel approach of cancer therapy. J Med Chem 52:6782–6789CrossRefGoogle Scholar
  30. Paris M, Porcelloni M, Binaschi M, Fattori D (2008) Histone deacetylase inhibitors: from bench to clinic. J Med Chem 51:1505–1529CrossRefGoogle Scholar
  31. Premanand C, Rema M, Sameer MZ, Sujatha M, Balasubramanvam M (2009) Inhibitory effect of curcuminoids on acetylcholinesterase activity and attenuation of scopolamine-induced amnesia may explain medicinal use of turmeric in Alzheimer's disease. Pharm Biochem Behav 91:554–559CrossRefGoogle Scholar
  32. Puneeth HR, Ananda H, Kumar KSS, Rangappa KS, Sharada AC (2016) Synthesis and antiproliferative studies of curcumin pyrazole derivatives. Med Chem Res 25:1842–1851CrossRefGoogle Scholar
  33. Ravichandiran P, Jegan A, Premnath D, Periasamy VS, Vasanthkumar S (2015) Design, synthesis, molecular docking as histone deacetylase (HDAC8) inhibitors, cytotoxicity and antibacterial evaluation of novel 6-(4-(4-aminophenylsulfonyl)phenylamino)-5H-benzo[a]phenoxazin-5-one derivatives. Med Chem Res 24:197–208CrossRefGoogle Scholar
  34. Ruby AJ, Kuttan G, Babu KD, Rajasekharan KN, Kuttan R (1995) Anti-tumour and antioxidant activity of natural curcuminoids. Cancer Lett 94:79–83CrossRefGoogle Scholar
  35. Sahu PK, Sahu PK, Gupta SK, Thavaselvam D, Agarwal DD (2012) Synthesis and evaluation of antimicrobial activity of 4H-pyrimido[2,1-b] benzothiazole, pyrazole and benzylidene derivatives of curcumin. Eur J Med Chem 54:366–378CrossRefGoogle Scholar
  36. Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Model 17:57–61Google Scholar
  37. Selvam C, Jachak SM, Thilagavathi R, Chakraborti AK (2005) Design, synthesis, biological evaluation and molecular docking of curcumin analogues as antioxidant, cyclooxygenase inhibitory and anti-inflammatory agents. Bioorg Med Chem Lett 15:1793–1797CrossRefGoogle Scholar
  38. Senawong T, Wongphakham P, Saiwichai T, Phaosiri C, Kumboonma P (2015) Histone deacetylase inhibitory activity of hydroxycapsaicin, a synthetic derivative of capsaicin, and its cytotoxic effects against human colon cancer cell lines. Turk J Biol 39:1–10CrossRefGoogle Scholar
  39. Sharma R, Jadav SS, Yasmin S, Bhatia S, Khalilullah H, Ahsan MJ (2015) Simple, efficient, and improve synthesis of Biginelli-type compounds of curcumin as anticancer agents. Med Chem Res 24:636–644CrossRefGoogle Scholar
  40. Suzuki T, Miyata N (2005) Non-hydroxamate histone deacetylase inhibitors. Curr Med Chem 12:2867–2880CrossRefGoogle Scholar
  41. Tatar GB, Erden DD, Demir AS, Dalkara S, Yelekci K, Yurter HE (2009) Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: activity and docking studies. Bioorg Med Chem 17:5219–5228CrossRefGoogle Scholar
  42. Thapliyal R, Maru GB (2001) Inhibition of Cytochrome P450 isozymes by curcumins in vitro and in vivo. Food Chem Toxicol 39:541–547CrossRefGoogle Scholar
  43. Tӧnnies E Trushina E (2017) Oxidative stress,synaptic dysfunction,and Alzheimer’s disease. J Alzheimer Dis 57:1105–1121CrossRefGoogle Scholar
  44. Venkateswarlu S, Ramachandra MS, Subbaraju GV (2005) Synthesis and biological evaluation of polyhydroxycurcuminoids. Bioorg Med Chem 13:6374–6380CrossRefGoogle Scholar
  45. Weichert W (2009) HDAC expression and clinical prognosis inhuman malignancies. Cancer Lett 280:168–176CrossRefGoogle Scholar
  46. Zhang L, Minyong L, Jinhong F, Hao F, Wenfang X (2012) Discovery of a novel histone deacetylase 8 inhibitor. Med Chem Res 21:152–156CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Natural Products Research Unit, Center of Excellence for Innovation in Chemistry, Ministry of Higher Education, ScienceResearch and Innovation (Implementation Unit-IU, Khon Kaen University), Department of Chemistry, Faculty of Science, Khon Kaen UniversityKhon KaenThailand
  2. 2.Natural Products Research Unit, Department of Biochemistry, Faculty of ScienceKhon Kaen UniversityKhon KaenThailand

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