Synthesis of New Zerumbone Hydrazones and Their In-vitro Anticancer Activity

Author(s): Vu V. Vu, Tran K. Vu*

Journal Name: Current Bioactive Compounds

Volume 17 , Issue 4 , 2021


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: A series of new zerumbone hydrazones 5a-f and 9a-f have been synthesized in via an in situ procedure in high yields. The structure of synthesized compounds has been confirmed using 1H, 13C NMR and HR-MS. The bioassay result showed that several compounds exhibited cytotoxic effects against three human cancer cell lines, including HepG-2, SK-LU-1, and MCF-7. Compound 9a showed the best cytotoxic effect against HepG-2, SK-LU-1, and MCF-7 with IC50 values of 8.20, 6.66, and 9.35 μM, respectively.

Objective: This study aims at developing new zerumbone hydrazones as anticancer agents based on zerumbone, a natural compound wildly growing in Vietnam.

Methods: A series of new zerumbone hydrazones was designed, synthesized, and evaluated for cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7, and SKLu-1, using the MTT method.

Results: The bioassay result showed that several compounds exhibited cytotoxic effects against three human cancer cell lines, including HepG-2, SK-LU-1, and MCF-7. Especially, compound 9a displayed the best cytotoxic effect against HepG-2, SK-LU-1, and MCF-7 with IC50 values of 8.20, 6.66, and 9.35 μM, respectively.

Conclusion: The research results suggest that some compounds could be considered as leads for the future design of zerumbone hydrazones in which bio-isosteric replacements in theortho position of the phenyl ring could be performed to improve the cytotoxic activity.

Keywords: Zerumbone, hydrazone, cytotoxicity, anticancer, synthesis, derivatives.

[1]
Dung, N.X.; Chinh, T.D.; Rang, D.D.; Leclereq, P.A. The constituents of the rhizome oil of Zingiber zerumbet (L.) Sm. from Vietnam. J. Essent. Oil Res., 1993, 5, 553-555.
[http://dx.doi.org/10.1080/10412905.1993.9698277]
[2]
Murakami, A.; Takahashi, D.; Kinoshita, T.; Koshimizu, K.; Kim, H.W.; Yoshihiro, A.; Nakamura, Y.; Jiwajinda, S.; Terao, J.; Ohigashi, H. Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: The α,β-unsaturated carbonyl group is a prerequisite. Carcinogenesis, 2002, 23(5), 795-802.
[http://dx.doi.org/10.1093/carcin/23.5.795] [PMID: 12016152]
[3]
Huang, G.C.; Chien, T.Y.; Chen, L.G.; Wang, C.C. Antitumor effects of zerumbone from Zingiber zerumbet in P-388D1 cells in vitro and in vivo. Planta Med., 2005, 71(3), 219-224.
[http://dx.doi.org/10.1055/s-2005-837820] [PMID: 15770541]
[4]
Alwi, S.; Sakinah, S.; Nallappan, M.; Pihie, A.; Hawariah, L. Malaysian. Zerumbone exerts antiproliferative activity in via apoptosis on HepG2 cell Malaysian. J. Biochem. Mol. Biol., 2007, 15, 19-23.
[5]
Jantan, I.; Rafi, I.A.A.; Jalil, J. Platelet-Activating Factor (PAF) receptor-binding antagonist activity of Malaysian medicinal plants. Phytomedicine, 2005, 12(1-2), 88-92.
[http://dx.doi.org/10.1016/j.phymed.2003.06.006] [PMID: 15693713]
[6]
Dai, J.R.; Cardellina, J.H.; McMahon, J.B.; Boyd, M.R. Zerumbone, an HIV-inhibitory and cytotoxic sesquiterpene of Zingiber aromaticum and Z. zerumbet. Nat. Prod. Lett., 1997, 10, 115-118.
[http://dx.doi.org/10.1080/10575639708043725]
[7]
Kitayama, T.; Masuda, T.; Sakai, K.; Imada, C.; Yonekura, Y.; Kawai, Y. Remarkable synthesis and structure of allene type zerumbone. Tetrahedron, 2006, 62, 10859-10864.
[http://dx.doi.org/10.1016/j.tet.2006.08.102]
[8]
Kitayama, T.; Okamoto, T.; Hill, R.K.; Kawai, Y.; Takahashi, S.; Yonemori, S.; Yamamoto, Y.; Ohe, K.; Uemura, S.; Sawada, S. Chemistry of Zerumbone. 1. simplified isolation, conjugate addition reactions, and a unique ring contracting transannular reaction of its dibromide. J. Org. Chem., 1999, 64(8), 2667-2672.
[http://dx.doi.org/10.1021/jo981593n] [PMID: 11674334]
[9]
Ohe, K.; Miki, K.; Tanaka, T.; Sawada, S.; Uemura, S. Selective conjugate addition to Zerumbone and transannular cyclization of its derivatives. J. Chem. Soc. Perkin Trans., 2000, 1, 3627-3634.
[http://dx.doi.org/10.1039/b004284f]
[10]
Kitayama, T.; Yokoi, T.; Kawai, Y.; Hill, R.K.; Morita, M.; Okamoto, T.; Yamamoto, Y.; Fokin, V.V.; Sharpless, K.B.; Sawada, S. The chemistry of Zerumbone. Part 5: Structural transformation of the dimethylamine derivatives. Tetrahedron, 2003, 59, 4857-4866.
[http://dx.doi.org/10.1016/S0040-4020(03)00667-7]
[11]
Kitayama, T.; Masuda, T.; Kawai, Y.; Hill, R.K.; Takatani, M.; Sawada, S.; Okamoto, T. The chemistry of Zerumbone. Part 3: Stereospecific creation of five stereogenic centers by double Sharpless oxidation. Tetrahedron Asymmetry, 2001, 12, 2805-2810.
[http://dx.doi.org/10.1016/S0957-4166(01)00505-5]
[12]
Kitayama, T.; Nagao, R.; Masuda, T.; Hill, R.K.; Morita, M.; Takatani, M.; Sawada, S.; Okamoto, T. The chemistry of Zerumbone IV: Asymmetric synthesis of Zerumbol. J. Mol. Catal., B Enzym., 2002, 17, 75-79.
[http://dx.doi.org/10.1016/S1381-1177(02)00009-7]
[13]
Kitayama, T.; Saito, A.; Ohta, S.; Awata, M. Efficient synthesis of an optically active tetrahydrozerumbone exhibiting a fragrance and the application of Zerumbone derivatives with a medium ring structure. Tetrahedron Asymmetry, 2012, 23, 1490-1495.
[http://dx.doi.org/10.1016/j.tetasy.2012.09.016]
[14]
Kitayama, T.; Ohta, S.; Kawai, Y.; Nakayama, N.; Awata, M. Synthesis of optically active tetrahydrozerumbone. Tetrahedron Asymmetry, 2010, 21, 11-15.
[http://dx.doi.org/10.1016/j.tetasy.2009.11.030]
[15]
Kitayama, T.; Awata, M.; Kawai, Y.; Tsuji, A.; Yoshida, Y. Asymmetric synthesis of versatile monoepoxyzerumbone and monoepoxyzerumbol. Tetrahedron Asymmetry, 2008, 19, 2367-2373.
[http://dx.doi.org/10.1016/j.tetasy.2008.10.002]
[16]
Kitayama, T.; Yoshida, Y.; Furukawa, J.; Kawai, Y.; Sawada, S. Asymmetric synthesis of triepoxyzerumbol. Tetrahedron Asymmetry, 2007, 18, 1676-1681.
[http://dx.doi.org/10.1016/j.tetasy.2007.07.013]
[17]
Murakami, A.; Takahashi, D.; Koshimizu, K.; Ohigashi, H. Synergistic suppression of superoxide and nitric oxide generation from inflammatory cells by combined food factors. Mutat. Res., 2003, 523-524, 151-161.
[http://dx.doi.org/10.1016/S0027-5107(02)00331-7] [PMID: 12628513]
[18]
Takada, Y.; Murakami, A.; Aggarwal, B.B. Zerumbone abolishes NF-kappaB and IkappaBalpha kinase activation leading to suppression of antiapoptotic and metastatic gene expression, upregulation of apoptosis, and downregulation of invasion. Oncogene, 2005, 24(46), 6957-6969.
[http://dx.doi.org/10.1038/sj.onc.1208845] [PMID: 16007145]
[19]
Nakamura, Y.; Yoshida, C.; Murakami, A.; Ohigashi, H.; Osawa, T.; Uchida, K. Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes. FEBS Lett., 2004, 572(1-3), 245-250.
[http://dx.doi.org/10.1016/j.febslet.2004.07.042] [PMID: 15304356]
[20]
Rollas, S.; Küçükgüzel, S.G. Biological activities of hydrazone derivatives. Molecules, 2007, 12(8), 1910-1939.
[http://dx.doi.org/10.3390/12081910] [PMID: 17960096]
[21]
Chaudhari, H.K.; Siddikia, A.A.; Manohara, Y.D. Design and synthesis of novel oxadiazole and diphenyl ether hydrazone derivatives of coumarin as potential antibacterial agents. Curr. Bioact. Compd., 2017, 13, 318-325.
[http://dx.doi.org/10.2174/1573407213666161128121435]
[22]
Lima, P.C.; Lima, L.M.; da Silva, K.C.; Léda, P.H.; de Miranda, A.L.; Fraga, C.A.M.; Barreiro, E.J. Synthesis and analgesic activity of novel N-acylarylhydrazones and isosters, derived from natural safrole. Eur. J. Med. Chem., 2000, 35(2), 187-203.
[http://dx.doi.org/10.1016/S0223-5234(00)00120-3] [PMID: 10758281]
[23]
Kalsi, R.; Shrimali, M.; Bhalla, T.N.; Barthwal, J.P. Indian J. Pharm. Sci., 2006, 41, 353.
[24]
Silva, G.A.; Costa, L.M.M.; Brito, F.C.F.; Miranda, A.L.P.; Barreiro, E.J.; Fraga, C.A.M. New class of potent antinociceptive and antiplatelet 10H-phenothiazine-1-acylhydrazone derivatives. Bioorg. Med. Chem., 2004, 12(12), 3149-3158.
[http://dx.doi.org/10.1016/j.bmc.2004.04.009] [PMID: 15158783]
[25]
Savini, L.; Chiasserini, L.; Travagli, V.; Pellerano, C.; Novellino, E.; Cosentino, S.; Pisano, M.B. New α-(N)-heterocyclichydrazones: Evaluation of anticancer, anti-HIV and antimicrobial activity. Eur. J. Med. Chem., 2004, 39(2), 113-122.
[http://dx.doi.org/10.1016/j.ejmech.2003.09.012] [PMID: 14987820]
[26]
Bijev, A. New heterocyclic hydrazones in the search for antitubercular agents: Synthesis and in vitro evaluations. Lett. Drug Descrip. Discovery (Read.), 2006, 3, 506-512.
[27]
Loncle, C.; Brunel, J.M.; Vidal, N.; Dherbomez, M.; Letourneux, Y. Synthesis and antifungal activity of cholesterol-hydrazone derivatives. Eur. J. Med. Chem., 2004, 39(12), 1067-1071.
[http://dx.doi.org/10.1016/j.ejmech.2004.07.005] [PMID: 15571868]
[28]
Abdel-Aal, M.T.; El-Sayed, W.A.; El-Ashry, S.H. Synthesis and antiviral evaluation of some sugar arylglycinoylhydrazones and their oxadiazoline derivatives. Arch. Pharm. (Weinheim), 2006, 339(12), 656-663.
[http://dx.doi.org/10.1002/ardp.200600100] [PMID: 17149795]
[29]
Figarella, K.; Marsiccobetre, S.; Galindo-Castro, I.; Urdaneta, N.; Herrera, J.C.; Canudas, N.; Galarraga, E. Antileishmanial and antitrypanosomal activity of synthesized hydrazones, pyrazoles, pyrazolo[1,5-a]-pyrimidines and pyrazolo[3,4-b]-. Pyridine. Curr. Bioact. Compd., 2018, 14, 234-239.
[http://dx.doi.org/10.2174/1573407213666170405121810]
[30]
Scudiero, D.A.; Shoemaker, R.H.; Paull, K.D.; Monks, A.; Tierney, S.; Nofziger, T.H.; Currens, M.J.; Seniff, D.; Boyd, M. Feasibility of drug screening with panels of human tumor cell lines using a Microculture tetrazolium assay. Cancer Res., 1988, 48, 4827-4833.
[PMID: 3409223]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 4
Year: 2021
Published on: 30 June, 2020
Page: [331 - 338]
Pages: 8
DOI: 10.2174/1573407216999200630133625
Price: $65

Article Metrics

PDF: 43
HTML: 1