Suppression of PGE2 production via disruption of MAPK phosphorylation by unsymmetrical dicarbonyl curcumin derivatives
- 108 Downloads
Curcumin is an important molecule found in turmeric plants and has been reported to exhibit some profound anti-inflammatory activities by interacting with several important molecular targets found in the mitogen-activated protein kinase and NF-κβ pathways. As part of our continuing effort to search for new anti-inflammatory agents with better in vitro and in vivo efficacies, we have synthesized a series of new unsymmetrical dicarbonyl curcumin derivatives and tested their effects on prostaglandin E2 secretion level in interferon-γ/lipopolysaccharide-activated macrophage cells. Among those, five compounds exhibited remarkable suppression on prostaglandin E2 production with IC50 values ranging from 0.87 to 18.41 µM. The most potent compound 17f was found to down-regulate the expression of cyclooxygenase-2 mRNA suggesting that this series of compounds could possibly target the mitogen-activated protein kinase signal transduction pathway. Whilst the compound did not affect the expression of the conventional mitogen-activated protein kinases, the results suggest that it could disrupt the phosphorylation and activation of the proteins particularly the c-Jun N-terminal kinases. Finally, the binding interactions were examined using the molecular docking and dynamics simulation approaches.
KeywordsProstaglandin E2 COX-2 mRNA expression MAPK phosphorylation Molecular Dynamic simulation Unsymmetrical dicarbonyl curcumin derivatives
This work was financially supported by ScienceFund (02-01-02-SF00665), Ministry of Science, Technology & Innovation, Malaysia and FRGS (FRGS/2/2014/ST01/UKM/02/3), Ministry of High Education, Malaysia. Authors also thank Universiti Kebangsaan Malaysia for the funds provided under the Research University Grant UKM-DIP-2014-16.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Bukhari SNA, Lauro G, Jantan I, Bifulco G, Amjad MW (2014) Pharmacological evaluation and docking studies of α,β-unsaturated carbonyl based synthetic compounds as inhibitors of secretory phospholipase A2, cyclooxygenases, lipoxygenase and proinflammatory cytokines. Bioorganic Med Chem 22(15):4151–4161CrossRefGoogle Scholar
- Ireson C, Orr S, Jones DJ, Verschoyle R, Lim CK, Luo JL, Howells L, Plummer S, Jukes R, Williams M, Steward WP, Gescher A (2001) Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production. Cancer Res 61(3):1058–1064PubMedGoogle Scholar
- Ireson CR, Jones DJ, Orr S, Coughtrie MW, Boocock DJ, Williams ML, Farmer PB, Steward WP, Gescher AJ (2002) Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol Biomark Prev 11(1):105–111Google Scholar
- Leong SW, Faudzi SMM, Abas F, Aluwi MFFM, Rullah K, Lam KW, Bahari MNA, Ahmad S, Tham CL, Shaari K, Lajis NH (2015) Nitric oxide inhibitory activity and antioxidant evaluations of 2-benzoyl-6-benzylidenecyclohexanone analogs, a novel series of curcuminoid and diarylpentanoid derivatives. Bioorganic Med Chem Lett 25(16):3330–3337CrossRefGoogle Scholar
- Mohd Aluwi MFF, Rullah K, Yamin BM, Leong SW, Abdul Bahari MN, Lim SJ, Mohd Faudzi SM, Jalil J, Abas F, Mohd Fauzi N, Ismail NH, Jantan I, Lam KW (2016) Synthesis of unsymmetrical monocarbonyl curcumin analogs with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines. Bioorganic Med Chem Lett 26(10):2531–2538Google Scholar
- Sandur SK, Pandey MK, Sung B, Ahn KS, Murakami A, Sethi G, Limtrakul P, Badmaev V, Aggarwal BB (2007) Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis 28(8):1765–1773CrossRefPubMedGoogle Scholar
- Tham CL, Hazeera Harith H, Wai Lam K, Joong Chong Y, Singh Cheema M, Roslan Sulaiman M, Hj Lajis N, Ahmad Israf D (2015) The synthetic curcuminoid BHMC restores endotoxin-stimulated HUVEC dysfunction:specific disruption on enzymatic activity of p38 MAPK. Eur J Pharmacol 749:1–11CrossRefPubMedGoogle Scholar
- Tham CL, Lam KW, Rajajendram R, Cheah YK, Sulaiman MR, Lajis NH, Kim MK, Israf DA (2011) The effects of a synthetic curcuminoid analog, 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone on proinflammatory signaling pathways and CLP-induced lethal sepsis in mice. Eur J Pharmacol 652(1–3):136–144CrossRefPubMedGoogle Scholar
- Yang JY, Zhang LJ, Zhao SQ, Yuan D, Lian GN, Wang XX, Zhang HT, Wang LH, Wu CF (2010) Demethoxycurcumin, bisdemethoxycurcumin, two natural derivatives of curcumin, attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NFκB signaling pathways in N9 microglia induced by lipopolysaccharide. Neurosci Res 68(Supplement 1):e451–e452Google Scholar