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Current Pharmaceutical Biotechnology

Author(s): Rafael Claudino dos Santos, Raquel Oliveira Nascimento de Freitas, Mary Ann Foglio, João Ernesto de Carvalho, Ana Lucia Tasca Góes Ruiz, Lucas Roberto Pessatto, Rodrigo Juliano Oliveira*, Adrivanio Baranoski, Bruna Isabela Biazi, Mário Sérgio Mantovani, Candida Aparecida Leite Kassuya, Pedro Cruz de Oliveira Junior and Anelise Samara Nazari Formagio*

DOI: 10.2174/1389201023666211217150837

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Synthesis, Characterization, Antiproliferative Activity of Galloyl Derivatives and Investigation of Cytotoxic Properties in HepG2/C3A Cells

Page: [1623 - 1633] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Appropriate substituents in the galloyl group could lead to significant biological properties.

Objectives: Novel galloyl-substituted compounds bearing 2-substituted-1, 3, 4-oxadiazol-5-yl, 5- substituted-1,2,4-triazol-3-yl, and carboxamide groups were synthesized and evaluated for their antiproliferative activity. Additionally, galloyl hydrazide (2) was evaluated by performing cytotoxicity, membrane integrity, cell cycle, and apoptosis assays in HepG2/C3A cells.

Methods: General procedure was used for the synthesis of galloyl-substituted (3-9, 11) and characterized by their spectroscopic data (1H and 13C NMR). The antiproliferative activity of all novel galloyl derivatives was evaluated against nine human tumors and one nontumoral cell line. Three response parameters (GI50, TGI, and LC50) were calculated. The cytotoxicity test was performed for the resazurin assay. The membrane integrity, cell cycle, and apoptosis assays were performed by flow cytometry.

Results: The substitution of the methoxy group of the galloyl ring system for a carboxamide group (3, 4, 5, and 6) produced compounds with moderate antitumoral activity, particularly 6, against six human cancer cell lines, K-562, PC-3, NCI-ADR/RES, OVCAR, 786-0 and NCI-H460, with GI50 values ≤ 9.45 μg/mL. Triazole derivatives 7 and 8 exhibited higher antitumoral activity toward OVCAR, MCF-7 and leukemia K-562 cell lines, exhibiting GI50 values less than 10 μg/mL. Compound 11 displayed significant activity against PC-3 (GI50 = 4.31 μg/mL), OVCAR (GI50 = 8.84 μg/mL) and K-562 (GI50 = 8.80 μg/mL) cell lines. Galloyl hydrazide (2) had cytotoxic activity in HepG2/C3A cells (IC50 = 153.7 μg/mL). In membrane permeability, cell count, cell cycle, and apoptosis assays, as determined using the IC50 of compound (2) in HepG2/C3A cells, increased membrane permeability, decreased cell count, altered cell cycle, and initial apoptosis was observed compared to the control group.

Conclusion: Thus, our results showed for the first time the synthesis, antiproliferative activity, and cytotoxicity of galloyl-substituted compounds. Galloyl-substitution does not have a very strong synergistic effect in the inhibition of cancer cell proliferation compared with galloyl hydrazide (2). Compound 2 demonstrated promising activity in HepG2/C3A hepatocarcinoma cells.

Keywords: Galloyl, hydrazide, oxadiazole, triazole, antitumoral activity, hepatocarcinoma.

Graphical Abstract

[1]
Chen, H.M.; Wu, Y.C.; Chia, Y.C.; Chang, F.R.; Hsu, H.K.; Hsieh, Y.C.; Chen, C.C.; Yuan, S.S. Gallic acid, a major component of Toona sinensis leaf extracts, contains a ROS-mediated anti-cancer activity in human prostate cancer cells. Cancer Lett., 2009, 286(2), 161-171.
[http://dx.doi.org/10.1016/j.canlet.2009.05.040] [PMID: 19589639]
[2]
Hou, A.J.; Peng, L.Y.; Liu, Y.Z.; Lin, Z.W.; Sun, H.D. Gallotannins and related polyphenols from Pistacia weinmannifolia. Planta Med., 2000, 66(7), 624-626.
[http://dx.doi.org/10.1055/s-2000-8633] [PMID: 11105566]
[3]
Inoue, M.; Suzuki, R.; Sakaguchi, N.; Li, Z.; Takeda, T.; Ogihara, Y.; Jiang, B.Y.; Chen, Y. Selective induction of cell death in cancer cells by gallic acid. Biol. Pharm. Bull., 1995, 18(11), 1526-1530.
[http://dx.doi.org/10.1248/bpb.18.1526] [PMID: 8593472]
[4]
Kaur, M.; Velmurugan, B.; Rajamanickam, S.; Agarwal, R.; Agarwal, C. Gallic acid, an active constituent of grape seed extract, exhibits anti-proliferative, pro-apoptotic and anti-tumorigenic effects against prostate carcinoma xenograft growth in nude mice. Pharm. Res., 2009, 26(9), 2133-2140.
[http://dx.doi.org/10.1007/s11095-009-9926-y] [PMID: 19543955]
[5]
Reddy, T.C.; Aparoy, P.; Babu, N.K.; Kumar, K.A.; Kalangi, S.K.; Reddanna, P. Kinetics and docking studies of a COX-2 inhibitor isolated from Terminalia bellerica fruits. Protein Pept. Lett., 2010, 17(10), 1251-1257.
[http://dx.doi.org/10.2174/092986610792231537] [PMID: 20441561]
[6]
Chandramohan Reddy, T.; Bharat Reddy, D.; Aparna, A.; Arunasree, K.M.; Gupta, G.; Achari, C.; Reddy, G.V.; Lakshmipathi, V.; Subramanyam, A.; Reddanna, P. Anti-leukemic effects of gallic acid on human leukemia K562 cells: downregulation of COX-2, inhibition of BCR/ABL kinase and NF-κB inactivation. Toxicol. In Vitro, 2012, 26(3), 396-405.
[http://dx.doi.org/10.1016/j.tiv.2011.12.018] [PMID: 22245431]
[7]
Veluri, R.; Singh, R.P.; Liu, Z.; Thompson, J.A.; Agarwal, R.; Agarwal, C. Fractionation of grape seed extract and identification of gallic acid as one of the major active constituents causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells. Carcinogenesis, 2006, 27(7), 1445-1453.
[http://dx.doi.org/10.1093/carcin/bgi347] [PMID: 16474170]
[8]
Yeh, R.D.; Chen, J.C.; Lai, T.Y.; Yang, J.S.; Yu, C.S.; Chiang, J.H.; Lu, C.C.; Yang, S.T.; Yu, C.C.; Chang, S.J.; Lin, H.Y.; Chung, J.G. Gallic acid induces G0/G1 phase arrest and apoptosis in human leukemia HL-60 cells through inhibiting cyclin D and E, and activating mitochondria-dependent pathway. Anticancer Res., 2011, 31(9), 2821-2832.
[PMID: 21868525]
[9]
Lewandowska, U.; Szewczyk, K.; Hrabec, E.; Janecka, A.; Gorlach, S. Overview of metabolism and bioavailability enhancement of polyphenols. J. Agric. Food Chem., 2013, 61(50), 12183-12199.
[http://dx.doi.org/10.1021/jf404439b] [PMID: 24295170]
[10]
da Silva, M.M.; Comin, M.; Duarte, T.S.; Foglio, M.A.; de Carvalho, J.E.; do Vieira, M.C.; Formagio, A.S.N. Synthesis, antiproliferative activity and molecular properties predictions of galloyl derivatives. Molecules, 2015, 20(4), 5360-5373.
[http://dx.doi.org/10.3390/molecules20045360] [PMID: 25816079]
[11]
Chaubal, R.; Deshapande, V.H.; Deshpande, N.R. Methyl gallate, the medicinally important compound: a review. J. Environ. Agric. Food Chem., 2005, 4, 956-962.
[12]
Fiuza, S.M.; Gomes, C.; Teixeira, L.J.; Girão da Cruz, M.T.; Cordeiro, M.N.; Milhazes, N.; Borges, F.; Marques, M.P. Phenolic acid derivatives with potential anticancer properties--a structure-activity relationship study. Part 1: methyl, propyl and octyl esters of caffeic and gallic acids. Bioorg. Med. Chem., 2004, 12(13), 3581-3589.
[http://dx.doi.org/10.1016/j.bmc.2004.04.026] [PMID: 15186842]
[13]
Hsieh, T.J.; Liu, T.Z.; Chia, Y.C.; Chern, C.L.; Lu, F.J.; Chuang, M.C.; Mau, S.Y.; Chen, S.H.; Syu, Y.H.; Chen, C.H. Protective effect of methyl gallate from Toona sinensis (Meliaceae) against hydrogen peroxide-induced oxidative stress and DNA damage in MDCK cells. Food Chem. Toxicol., 2004, 42(5), 843-850.
[http://dx.doi.org/10.1016/j.fct.2004.01.008] [PMID: 15046831]
[14]
Kamatham, S.; Kumar, N.; Gudipalli, P. Isolation and characterization of gallic acid and methyl gallate from the seed coats of Givotia rottleriformis Griff. and their anti-proliferative effect on human epidermoid carcinoma A431 cells. Toxicol. Rep., 2015, 2, 520-529.
[http://dx.doi.org/10.1016/j.toxrep.2015.03.001] [PMID: 28962387]
[15]
Lee, H.; Lee, H.; Kwon, Y.; Lee, J.H.; Kim, J.; Shin, M.K.; Kim, S.H.; Bae, H. Methyl gallate exhibits potent antitumor activities by inhibiting tumor infiltration of CD4+CD25+ regulatory T cells. J. Immunol., 2010, 185(11), 6698-6705.
[http://dx.doi.org/10.4049/jimmunol.1001373] [PMID: 21048105]
[16]
Lee, S.H.; Kim, J.K.; Kim, D.W.; Hwang, H.S.; Eum, W.S.; Park, J.; Han, K.H.; Oh, J.S.; Choi, S.Y. Antitumor activity of methyl gallate by inhibition of focal adhesion formation and Akt phosphorylation in glioma cells. Biochim. Biophys. Acta, 2013, 1830(8), 4017-4029.
[http://dx.doi.org/10.1016/j.bbagen.2013.03.030] [PMID: 23562553]
[17]
Lizárraga, D.; Touriño, S.; Reyes-Zurita, F.J.; de Kok, T.M.; van Delft, J.H.; Maas, L.M.; Briedé, J.J.; Centelles, J.J.; Torres, J.L.; Cascante, M. Witch hazel (Hamamelis virginiana) fractions and the importance of gallate moieties--electron transfer capacities in their antitumoral properties. J. Agric. Food Chem., 2008, 56(24), 11675-11682.
[http://dx.doi.org/10.1021/jf802345x] [PMID: 19035659]
[18]
Prabhu, R.; Mohammed, M.A.; Anjali, R.; Archunan, G.; Prabhu, N.M.; Pugazhendhi, A.; Suganthy, N. Ecofriendly one pot fabrication of methyl gallate@ZIF-L nanoscale hybrid as pH responsive drug delivery system for lung cancer therapy. Process Biochem., 2019, 84, 39-52.
[http://dx.doi.org/10.1016/j.procbio.2019.06.015]
[19]
Da Silva, S.L. Chaar, Jda.S.; Yano, T. Chemotherapeutic potential of two gallic acid derivative compounds from leaves of Casearia sylvestris Sw (Flacourtiaceae). Eur. J. Pharmacol., 2009, 608(1-3), 76-83.
[http://dx.doi.org/10.1016/j.ejphar.2009.02.004] [PMID: 19222998]
[20]
de Freitas, J.J.R.; da Silva, E.E.; Regueira, J.L.L.F.; de Andrade, S.A.; Calvalcante, P.M.M.; de Oliveira, R.N.; de Freitas Filho, J.R. 1,2,4-Oxadiazoles: Synthesis and applications. Rev. Virtual Quim, 2012, 4(6), 670-691.
[http://dx.doi.org/10.5935/1984-6835.20120051]
[21]
Huhtiniemi, T.; Suuronen, T.; Rinne, V.M.; Wittekindt, C.; Lahtela-Kakkonen, M.; Jarho, E.; Wallén, E.A.A.; Salminen, A.; Poso, A.; Leppänen, J. Oxadiazole-carbonylaminothioureas as SIRT1 and SIRT2 inhibitors. J. Med. Chem., 2008, 51(15), 4377-4380.
[http://dx.doi.org/10.1021/jm800639h] [PMID: 18642893]
[22]
Zhang, H.Z.; Kasibhatla, S.; Kuemmerle, J.; Kemnitzer, W.; Ollis-Mason, K.; Qiu, L.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S.X. Discovery and structure-activity relationship of 3-aryl-5-aryl-1,2,4-oxadiazoles as a new series of apoptosis inducers and potential anticancer agents. J. Med. Chem., 2005, 48(16), 5215-5223.
[http://dx.doi.org/10.1021/jm050292k] [PMID: 16078840]
[23]
Koryakova, A.G.; Ivanenkov, Y.A.; Ryzhova, E.A.; Bulanova, E.A.; Karapetian, R.N.; Mikitas, O.V.; Katrukha, E.A.; Kazey, V.I.; Okun, I.; Kravchenko, D.V.; Lavrovsky, Y.V.; Korzinov, O.M.; Ivachtchenko, A.V. Novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamides as selective GSK-3 inhibitors. Bioorg. Med. Chem. Lett., 2008, 18(12), 3661-3666.
[http://dx.doi.org/10.1016/j.bmcl.2007.11.121] [PMID: 18502121]
[24]
Gakh, A.A.; Sosnov, A.V.; Krasavin, M.; Nguyen, T.L.; Hamel, E. Identification of diaryl 5-amino-1,2,4-oxadiazoles as tubulin inhibitors: the special case of 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole. Bioorg. Med. Chem. Lett., 2013, 23(5), 1262-1268.
[http://dx.doi.org/10.1016/j.bmcl.2013.01.007] [PMID: 23385208]
[25]
Lei, X.; Danishefsky, S.J. Efficient synthesis of a novel resorcyclide as anticancer agent based on Hsp90 inhibition. Adv. Synth. Catal., 2008, 350(11-12), 1677-1681.
[http://dx.doi.org/10.1002/adsc.200800187] [PMID: 21442009]
[26]
Nahrwold, M.; Bogner, T.; Eissler, S.; Verma, S.; Sewald, N. “Clicktophycin-52”: a bioactive cryptophycin-52 triazole analogue. Org. Lett., 2010, 12(5), 1064-1067.
[http://dx.doi.org/10.1021/ol1000473] [PMID: 20131817]
[27]
Burlison, J.A.; Blagg, B.S.J. Synthesis and evaluation of coumermycin A1 analogues that inhibit the Hsp90 protein folding machinery. Org. Lett., 2006, 8(21), 4855-4858.
[http://dx.doi.org/10.1021/ol061918j] [PMID: 17020320]
[28]
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Ray, G.M.; Campbell, H.; Mayo, J.; Boyd, M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst., 1991, 83(11), 757-766.
[http://dx.doi.org/10.1093/jnci/83.11.757] [PMID: 2041050]
[29]
Zanetti, T.A.; Biazi, B.I.; Coatti, G.C.; Baranoski, A.; Marques, L.A.; Corveloni, A.C.; Mantovani, M.S. Mitotic spindle defects and DNA damage induced by dimethoxycurcumin lead to an intrinsic apoptosis pathway in HepG2/C3A cells. Toxicol. In Vitro, 2019, 61, 104643.
[http://dx.doi.org/10.1016/j.tiv.2019.104643] [PMID: 31513842]
[30]
Valdez, R.H.; Tonin, L.T.D.; Ueda-Nakamura, T.; Dias Filho, B.P.; Morgado-Diaz, J.A.; Sarragiotto, M.H.; Nakamura, C.V. Biological activity of 1,2,3,4-tetrahydro-β-carboline-3-carboxamides against Trypanosoma cruzi. Acta Trop., 2009, 110(1), 7-14.
[http://dx.doi.org/10.1016/j.actatropica.2008.11.008] [PMID: 19063858]
[31]
Formagio, A.S.N.; Tonin, L.T.D.; Foglio, M.A.; Madjarof, C.; de Carvalho, J.E.; da Costa, W.F.; Cardoso, F.P.; Sarragiotto, M.H. Synthesis and antitumoral activity of novel 3-(2-substituted-1,3,4-oxadiazol-5-yl) and 3-(5-substituted-1,2,4-triazol-3-yl) β-carboline derivatives. Bioorg. Med. Chem., 2008, 16(22), 9660-9667.
[http://dx.doi.org/10.1016/j.bmc.2008.10.008] [PMID: 18951806]
[32]
Savariz, F.C.; Formagio, A.S.N.; Barbosa, V.A.; Foglio, M.A.; De Carvalho, J.E.; Duarte, M.C.T.; Dias Filho, B.P.; Sarragiotto, M.H. Synthesis, antitumor and antimicrobial activity of novel 1-substituted phenyl-3-[3-alkylamino (methyl)-2-thioxo-1,3,4-oxadiazol-5-yl] β-carboline derivatives. J. Braz. Chem. Soc., 2010, 21(2), 288-298.
[http://dx.doi.org/10.1590/S0103-50532010000200014]
[33]
Nunes, D.M.; Pessatto, L.R.; Mungo, D.; Oliveira, R.J.; Pinto, L.M.C.; Iema, M.R.C.; Altei, W.F.; Martines, M.A.U.; Duarte, A.P. New complexes of usnate with lanthanides ions: La(III), Nd(III), Tb(III), Gd(III), synthesis, characterization, and investigation of cytotoxic properties in MCF-7 cells. Inorg. Chim. Acta, 2020, 506, 119546.
[http://dx.doi.org/10.1016/j.ica.2020.119546]
[34]
Navarro, S.D.; Pessatto, L.R.; Meza, A.; de Oliveira, E.J.T.; Auharek, S.A.; Vilela, L.C.; de Lima, D.P.; de Azevedo, R.B.; Kassuya, C.A.L.; Cáceres, O.I.A.; da Silva Gomes, R.; Beatriz, A.; Oliveira, R.J.; Martines, M.A.U. Resorcinolic lipid 3-heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one is a strategy for melanoma treatment. Life Sci., 2018, 209, 300-312.
[http://dx.doi.org/10.1016/j.lfs.2018.08.022] [PMID: 30102904]
[35]
Kopecký, J. Neurotoxicity and Immunotherapy. Klin. Onkol., 2020, 33(1), 11-14.
[http://dx.doi.org/10.14735/amko202011] [PMID: 32075382]
[36]
Kaczanowski, S. Apoptosis: its origin, history, maintenance and the medical implications for cancer and aging. Phys. Biol., 2016, 13(3), 031001.
[http://dx.doi.org/10.1088/1478-3975/13/3/031001] [PMID: 27172135]
[37]
Proskuryakov, S.Y.; Konoplyannikov, A.G.; Gabai, V.L. Necrosis: a specific form of programmed cell death? Exp. Cell Res., 2003, 283(1), 1-16.
[http://dx.doi.org/10.1016/S0014-4827(02)00027-7] [PMID: 12565815]