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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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General Review Article

Anti-Proliferative Potential of Fluorinated Curcumin Analogues: Experimental and Computational Analysis and Review of the Literature

Author(s): Mahdi Hatamipour, Farzin Hadizadeh, Mahmoud Reza Jaafari, Zahra Khashyarmanesh, Thozhukat Sathyapalan and Amirhossein Sahebkar*

Volume 29, Issue 8, 2022

Published on: 10 January, 2022

Page: [1459 - 1471] Pages: 13

DOI: 10.2174/0929867328666210910141316

Price: $65

Abstract

Background: Curcuminoids, flavoring, and coloring agents in food have potent antioxidant, anti-tumor activity, and anti-inflammatory effects. However, they are rapidly metabolized to lesser active metabolites. Therefore, various studies have been conducted to synthesize new and stable curcumin analogues with enhanced therapeutic activity.

Methods: Fluorinated curcumin compounds (2a-2f) were synthesized by Knoevenagel condensation between fluorobenzaldehydes (1a-1f) with curcumin. Fluorinated demethoxycurcumin (3a) was synthesized by condensation between demethoxycurcumin and 3,4-difluorobenzaldehyde (1f). The structures of these compounds were confirmed by FTIR, 1H-NMR, 13C-NMR, 19FNMR, and mass spectroscopy. Antiproliferative activities of these synthetic compounds were evaluated against breast cancer cells (4T1), melanoma cancer cells (B16F10), and normal cell lines (NIH 3T3) using MTT assay. The interaction of curcumin, 2f and 3a with several proteins (1HCL, 2ZOQ, 3D94, 5EW3, 4WA9, 1XKK, 6CCY) was investigated. The structural preservation of the epidermal growth factor receptor (EGFR) was investigated by molecular dynamics simulation.

Results: The spectroscopic data obtained confirmed the proposed structure of fluorinated analogues. The results showed that compounds 2f and 3a inhibited cancer cells proliferation significantly more than other compounds. Compounds 2f and 3a showed the highest affinity and lowest binding energy with EGFR. The binding energies were -7.8, -10, and - 9.8 kcal/mol for curcumin, 2f and 3a with EGFR, respectively. The molecular docking results demonstrated that compounds 2f and 3a were firmly bound in a complex with EGFR via the formation of a hydrogen bond.

Conclusion: In summary, we found that fluorinated demethoxycurcumin and fluorinated curcumin induces cancer cell death and binds to EGFR with high affinity.

Keywords: Curcumin, demethoxycurcumin, tumor, breast cancer, anti-proliferation, computational analysis.

« Previous
[1]
Hewlings, S.J.; Kalman, D.S. Curcumin: A Review of Its Effects on Human Health. Foods, 2017, 6(10), 92.
[http://dx.doi.org/10.3390/foods6100092] [PMID: 29065496]
[2]
Sadeghian, M.; Rahmani, S.; Jamialahmadi, T.; Johnston, T.P.; Sahebkar, A. The effect of oral curcumin supplementation on health-related quality of life: A systematic review and meta-analysis of randomized controlled trials. J. Affect. Disord., 2021, 278, 627-636.
[http://dx.doi.org/10.1016/j.jad.2020.09.091] [PMID: 33038707]
[3]
Ghandadi, M.; Sahebkar, A. Curcumin: An effective inhibitor of interleukin-6. Curr. Pharm. Des., 2017, 23(6), 921-931.
[http://dx.doi.org/10.2174/1381612822666161006151605] [PMID: 27719643]
[4]
Panahi, Y.; Khalili, N.; Sahebi, E.; Namazi, S.; Simental-Mendía, L.E.; Majeed, M.; Sahebkar, A. Effects of Curcuminoids Plus Piperine on Glycemic, Hepatic and Inflammatory Biomarkers in Patients with Type 2 Diabetes Mellitus: A Randomized Double-Blind Placebo-Controlled Trial. Drug Res. (Stuttg.), 2018, 68(7), 403-409.
[http://dx.doi.org/10.1055/s-0044-101752] [PMID: 29458218]
[5]
Hatamipour, M.; Johnston, T.P.; Sahebkar, A. One Molecule, Many Targets and Numerous Effects: The Pleiotropy of Curcumin Lies in its Chemical Structure Curr. Pharm. Des., 2018, 24(19), 2129-2136.
[http://dx.doi.org/10.2174/1381612824666180522111036] [PMID: 29788873]
[6]
Mohajeri, M.; Bianconi, V.; Ávila-Rodriguez, M.F.; Barreto, G.E.; Jamialahmadi, T.; Pirro, M.; Sahebkar, A. Curcumin: a phytochemical modulator of estrogens and androgens in tumors of the reproductive system. Pharmacol. Res., 2020, 156, 104765.
[http://dx.doi.org/10.1016/j.phrs.2020.104765] [PMID: 32217147]
[7]
Ghasemi, F.; Shafiee, M.; Banikazemi, Z.; Pourhanifeh, M.H.; Khanbabaei, H; Shamshirian, A.; Amiri Moghadam, S. ArefNezhad, R.; Sahebkar, A.; Avan, A.; Mirzaei, H. Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells. Pathol. Res. Pract., 2019, 215(10), 152556.
[http://dx.doi.org/10.1016/j.prp.2019.152556] [PMID: 31358480]
[8]
Anand, P.; Kunnumakkara, A.B.; Newman, R.A.; Aggarwal, B.B. Bioavailability of curcumin: problems and promises. Mol. Pharm., 2007, 4(6), 807-818.
[http://dx.doi.org/10.1021/mp700113r] [PMID: 17999464]
[9]
Sardjiman, S.; Reksohadiprodjo, M.; Hakim, L.; Van der Goot, H; Timmerman, H. 1, 5-Diphenyl-1, 4-pentadiene-3- ones and cyclic analogues as antioxidative agents. Synthesis and structure-activity relationship. Eur. J. Med. Chem., 1997, 32(7-8), 625-630.
[http://dx.doi.org/10.1016/S0223-5234(97)83288-6]
[10]
Tomren, M.A.; Másson, M.; Loftsson, T.; Tønnesen, H.H. Studies on curcumin and curcuminoids XXXI. Symmetric and asymmetric curcuminoids: stability, activity and complexation with cyclodextrin. Int. J. Pharm., 2007, 338(1-2), 27-34.
[http://dx.doi.org/10.1016/j.ijpharm.2007.01.013] [PMID: 17298869]
[11]
Fang, L.; Gou, S.; Liu, X.; Cao, F.; Cheng, L. Design, synthesis and anti-Alzheimer properties of dimethylaminomethyl-substituted curcumin derivatives. Bioorg. Med. Chem. Lett., 2014, 24(1), 40-43.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.011] [PMID: 24342238]
[12]
Fang, X.; Fang, L.; Gou, S.; Cheng, L. Design and synthesis of dimethylaminomethyl-substituted curcumin derivatives/analogues: potent antitumor and antioxidant activity, improved stability and aqueous solubility compared with curcumin. Bioorg. Med. Chem. Lett., 2013, 23(5), 1297-1301.
[http://dx.doi.org/10.1016/j.bmcl.2012.12.098] [PMID: 23357628]
[13]
Qiu, X.; Du, Y.; Lou, B.; Zuo, Y.; Shao, W.; Huo, Y.; Huang, J.; Yu, Y.; Zhou, B.; Du, J.; Fu, H.; Bu, X. Synthesis and identification of new 4-arylidene curcumin analogues as potential anticancer agents targeting nuclear factor-κB signaling pathway. J. Med. Chem., 2010, 53(23), 8260-8273.
[http://dx.doi.org/10.1021/jm1004545] [PMID: 21070043]
[14]
Smart, B.E. Introduction: fluorine chemistry. Chem. Rev., 1996, 5, 1555-1556.
[http://dx.doi.org/10.1021/cr960075e]
[15]
Padhye, S.; Yang, H.; Jamadar, A.; Cui, Q.C.; Chavan, D.; Dominiak, K.; McKinney, J.; Banerjee, S.; Dou, Q.P.; Sarkar, F.H. New difluoro Knoevenagel condensates of curcumin, their Schiff bases and copper complexes as proteasome inhibitors and apoptosis inducers in cancer cells. Pharm. Res., 2009, 26(8), 1874-1880.
[http://dx.doi.org/10.1007/s11095-009-9900-8] [PMID: 19421843]
[16]
Anand, P.; Thomas, S.G.; Kunnumakkara, A.B.; Sundaram, C.; Harikumar, K.B.; Sung, B.; Tharakan, S.T.; Misra, K.; Priyadarsini, I.K.; Rajasekharan, K.N.; Aggarwal, B.B. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem. Pharmacol., 2008, 76(11), 1590-1611.
[http://dx.doi.org/10.1016/j.bcp.2008.08.008] [PMID: 18775680]
[17]
Katsidoni, V.; Alexiou, P.; Fotiadou, M.; Pelecanou, M.; Sagnou, M.; Panagis, G. Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit morphine’s rewarding effect in rats. Psychopharmacology (Berl.), 2014, 231(23), 4467-4478.
[http://dx.doi.org/10.1007/s00213-014-3603-5] [PMID: 24838368]
[18]
Yodkeeree, S.; Chaiwangyen, W.; Garbisa, S. Limtrakul, PJTJonb Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit cancer cell invasion through the down-regulation of MMPs and uPA. 2009, 20(2), 87-95.
[19]
Liu, Y-L.; Yang, H-P.; Gong, L.; Tang, C-L.; Wang, H-J. Hypomethylation effects of curcumin, demethoxycurcumin and bisdemethoxycurcumin on WIF-1 promoter in non-small cell lung cancer cell lines. Mol. Med. Rep., 2011, 4(4), 675-679.
[20]
Shieh, J-M.; Chen, Y-C.; Lin, Y-C.; Lin, J-N.; Chen, W-C. Chen, Y-Y Demethoxycurcumin inhibits energy metabolic and oncogenic signaling pathways through AMPK activation in triple-negative breast cancer cells. J. Agric. Food Chem., 2013, 61(26), 6366-6375.
[http://dx.doi.org/10.1021/jf4012455] [PMID: 23777448]
[21]
Lin, H-Y.; Lin, J-N.; Ma, J-W.; Yang, N-S.; Ho, C-T.; Kuo, S-C. Demethoxycurcumin induces autophagic and apoptotic responses on breast cancer cells in photodynamic therapy. J. Funct. Foods, 2013, 12, 439-449.
[http://dx.doi.org/10.1016/j.jff.2014.12.014]
[22]
Knight, T.; Irving, J.A.E. Ras/Raf/MEK/ERK pathway activation in childhood acute lymphoblastic leukemia and its therapeutic targeting. Front. Oncol., 2014, 4, 160.
[http://dx.doi.org/10.3389/fonc.2014.00160] [PMID: 25009801]
[23]
Chohan, T.A.; Qian, H.; Pan, Y.; Chen, J-Z. Cyclin-dependent kinase-2 as a target for cancer therapy: progress in the development of CDK2 inhibitors as anti-cancer agents. Curr. Med. Chem., 2015, 22(2), 237-263.
[http://dx.doi.org/10.2174/0929867321666141106113633] [PMID: 25386824]
[24]
Verheul, H.M.; Pinedo, H.M. The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis and early clinical development of VEGF-receptor kinase inhibitors. Clin. Breast Cancer, 2000, 1(Suppl. 1), S80-S84.
[http://dx.doi.org/10.3816/CBC.2000.s.015] [PMID: 11970755]
[25]
Greuber, E.K.; Smith-Pearson, P.; Wang, J.; Pendergast, A.M. Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat. Rev. Cancer, 2013, 13(8), 559-571.
[http://dx.doi.org/10.1038/nrc3563] [PMID: 23842646]
[26]
Sigismund, S.; Avanzato, D.; Lanzetti, L. Emerging functions of the EGFR in cancer. Mol. Oncol., 2018, 12(1), 3-20.
[http://dx.doi.org/10.1002/1878-0261.12155] [PMID: 29124875]
[27]
Alwhaibi, A.; Verma, A.; Adil, M.S.; Somanath, P.R. The unconventional role of Akt1 in the advanced cancers and in diabetes-promoted carcinogenesis. Pharmacol. Res., 2019, 145, 104270.
[http://dx.doi.org/10.1016/j.phrs.2019.104270] [PMID: 31078742]
[28]
Vyas, A.; Dandawate, P.; Padhye, S.; Ahmad, A.; Sarkar, F. Perspectives on new synthetic curcumin analogs and their potential anticancer properties. Curr. Pharm. Des., 2013, 19(11), 2047-2069.
[PMID: 23116312]
[29]
Pisano, M.; Dettori, M.A.; Fabbri, D.; Delogu, G.; Palmieri, G.; Rozzo, C. Anticancer Activity of Two Novel Hydroxylated Biphenyl Compounds toward Malignant Melanoma Cells. Int. J. Mol. Sci., 2021, 22(11), 5636.
[http://dx.doi.org/10.3390/ijms22115636] [PMID: 34073232]
[30]
Khazaei Koohpar, Z.; Entezari, M.; Movafagh, A.; Hashemi, M. Anticancer activity of curcumin on human breast adenocarcinoma: Role of Mcl-1 gene. Iran. J. Cancer Prev., 2015, 8(3), e2331.
[http://dx.doi.org/10.17795/ijcp2331] [PMID: 26413251]
[31]
Dallakyan, S.; Olson, A.J. Small-molecule library screening by docking with PyRx. Chemical biology; Springer, 2015, pp. 243-250.
[32]
Dorai, T.; Gehani, N.; Katz, A. Therapeutic potential of curcumin in human prostate cancer. II. Curcumin inhibits tyrosine kinase activity of epidermal growth factor receptor and depletes the protein. Mol. Urol., 2000, 1, 1-6.
[PMID: 10851300]
[33]
Yim-im, W.; Sawatdichaikul, O.; Semsri, S.; Horata, N.; Mokmak, W.; Tongsima, S.; Suksamrarn, A.; Choowongkomon, K. Computational analyses of curcuminoid analogs against kinase domain of HER2. BMC Bioinformatics., 2014, 15(1), 261.
[http://dx.doi.org/10.1186/1471-2105-15-261] [PMID: 25089037]
[34]
Xu, Y-Y.; Cao, Y.; Ma, H.; Li, H-Q.; Ao, G-Z.J.B. chemistry m. Design, synthesis and molecular docking of α, β-unsaturated cyclohexanone analogous of curcumin as potent EGFR inhibitors with antiproliferative activity. Bioorg. Med. Chem., 2013, 21(2), 388-394.
[http://dx.doi.org/10.1016/j.bmc.2012.11.031] [PMID: 23245570]
[35]
Lobanov, M.Y.; Bogatyreva, N.S.; Galzitskaia, O.V. Radius of gyration is indicator of compactness of protein structure. Mol. Biol. (Mosk.), 2008, 42(4), 701-706.
[PMID: 18856071]

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