Synthesis and in vitro Evaluation of S-allyl Cysteine Ester - Caffeic Acid Amide Hybrids as Potential Anticancer Agents

Document Type : Research article

Authors

1 Química de Plantas Colombianas, Institute of Chemistry, Faculty of Exact and Natural Sciences, University of Antioquia (UdeA), Calle 70 No. 52–21, A.A 1226, Medellín, Colombia.

2 Grupo Impacto de los Componentes Alimentarios en la Salud, School of Nutrition and Dietetics, University of Antioquia (UdeA), A.A. 1226 Medellín.

3 Department of Inorganic and Organic Chemistry, University Jaume I, E-12071 Castellón, Spain.

4 Grupo de Micología Médica y Experimental, Corporación para Investigaciones Biológicas, Medellín, Colombia.

5 School of Health Sciences, Universidad Pontificia Bolivariana, Medellín, Colombia.

6 Grupo Impacto de los Componentes Alimentarios en la Salud, School of Nutrition and Dietetics, University of Antioquia

Abstract

We have synthesized a series of S-allyl cysteine ester-caffeic acid amide hybrids and evaluated them in order to determine their possible anticancer activity and selectivity in colorectal cancer, which is still one of the leading causes of morbidity and mortality worldwide. All compounds were tested against SW480 human colon adenocarcinoma cells and the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 6e, 9a, 9b, 9c and 9e exhibited the highest effect on viability (IC50 SW480-48h= 0.18, 0.12, 0.12, 0.11 and 0.12 mM, respectively) and selectivity (SI= 10.3, 1.5, >83.33, >90.91 and >83.33, respectively) in a time- and concentration-dependent manner. Besides, our results were even better as regards lead compounds (S-allyl cysteine and caffeic acid) and the standard drug (5-FU). Additionally, these five compounds induced mitochondrial depolarization that could be related with an apoptotic process. Moreover, hybrids 6e, 9a and 9e induced cell cycle arrest in G2/M phase, and compound 9c in S- phase, which suggests that these hybrid compounds could have also a cytostatic effect in SW480 cell line. The SAR analysis showed that hydroxyl groups increased the activity, besides, there was not a clear relationship between the antitumor properties and the length of the alkyl chain. Since hybrid compounds were much more selective than the conventional drug (5-FU), this make them promising candidates for further studies against colorectal cancer.

Keywords

Main Subjects


References
Pointet AL and Taieb J. Cáncer de colon. EMC -
Tratado De Med (2017) 21: 1–7
McQuade RM, Bornstein JC and Nurgali K. Anticolorectal cancer chemotherapy-induced diarrhoea:
current treatments and sideeffects. Int. J. Clin. Med.
(2014) 5: 393-406
Meunier B. Hybrid molecules with a dual mode of
action: dream or reality? Acc. Chem. Res. (2008) 41:
69–77
Tsogoeva SB. Recent progress in the development
of synthetic hybrids of natural or unnatural bioactive
compounds for medicinal chemistry. Mini Rev. Med.
Chem. (2010) 10: 773–93
Shaveta, Mishra S and Singh P. Hybrid molecules: the
privileged scaffolds for various pharmaceuticals. Eur.
J. Med. Chem. (2016) 124: 500–36.
Kim KM, Chun SB, Koo MS, Choi WJ, Kim TW, Kwon
YG, Chung HT, Billiar TR and Kim YM. Differential
regulation of NO availability from macrophages and
endothelial cells by the garlic component S-allyl
cysteine. Free Radic. Biol. Med. (2001) 30: 747-56
Ho SE, Ide N and Lau BH. S-allyl cysteine reduces
oxidant load in cells involved in the atherogenic
process. Phytomedicine (2001) 8: 39-46.
Numagami Y and Ohnishi ST. S-allylcysteine inhibits
free radical production, lipid peroxidation and
neuronal damage in rat brain ischemia. J. Nutr. (2001)
131: 1100S-5S
Numagami Y, Sato S and Ohnishi ST. Attenuation of
rat ischemic brain damage by aged garlic extracts:
a possible protecting mechanism as antioxidants.
Neurochem. Int. (1996) 29: 135-143.
Mostafa MG, Mima T, Ohnishi ST and Mori K.
S-allylcysteine ameliorates doxorubicin toxicity in the
heart and liver in mice. Planta Med. (2000) 66: 148–51
Welch C, Wuarin L and Sidell N. Antiproliferative
effect of the garlic compound S-allyl cysteine on
human neuroblastoma cells in-vitro. Cancer Lett.
(1992) 63: 211-9
Takeyama H, Hoon DS, Saxton RE, Morton DL and
Irie RF. Growth inhibition and modulation of cell
markers of melanoma by S-allyl cysteine. Oncology
(1993) 50: 63-9
Pinto JT, Qiao C, Xing J, Rivlin RS, Protomastro ML,
Weissler ML, Tao Y, Thaler H and Heston WD. Effects
of garlic thioallyl derivatives on growth, glutathione
concentration, and polyamine formation of human
prostate carcinoma cells in culture. Am. J. Clin. Nutr.
(1997) 66: 398-405
Liu Z, Li M, Chen K, Yang J, Chen R, Wang T, Liu J,
Yang W and Ye Z. S-allylcysteine induces cell cycle
arrest and apoptosis in androgen-independent human
prostate cancer cells. Mol. Med. Rep. (2012) 5: 439-43
Shirin H, Pinto JT, Kawabata Y, Soh JW, Delohery T,
Moss SF, Murty V, Rivlin RS, Holt PR and Weinstein IB.
Antiproliferative effects of S-allylmercaptocysteine on
colon cancer cells when tested alone or in combination
with sulindac sulfide. Cancer Res. (2001) 61: 725-31
Sumiyoshi H and Wargovich MJ. Chemoprevention
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
Anand P, Kunnumakkara AB, Sundaram C, Harikumar
KB, Tharakan ST, Lai OS, Sung B and Aggarwal BB.
Cancer is a preventable disease that requires major
lifestyle changes. Pharm. Res. (2008) 25: 2097-116
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre
LA and Jemal A. Global cancer statistics 2018:
GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries. CA Cancer
J. Clin. (2018) 1–31.
Arnold M, Sierra MS, Laversanne M, Soerjomataram
I, Jemal A and Bray F. Global patterns and trends in
colorectal cancer incidence and mortality. Gut (2017)
66:683-691
(1)
(2)
(3)
 Castrillón W et al. / IJPR (2019), 18 (4): 1770-1789
1788
of 1,2-dimethylhydrazine-induced colon cancer in
mice by naturally occurring organosulfur compounds.
Cancer Res. (1990) 50: 5084-7
Hung CC, Tsai WJ, Kuo LM and Kuo YH. Evaluation
of caffeic acid amide analogues as anti-platelet
aggregation and anti-oxidative agents. Bioorg. Med.
Chem. (2005) 13: 1791-7.
Son S and Lewis BA. Free radical scavenging and
antioxidative activity of caffeic acid amide and ester
analogues: structure-activity relationship. J. Agric.
Food Chem. (2002) 50:468-472.
Otero E, Robledo S, Díaz S, Carda M, Muñoz D,
Paños J, Vélez ID and Cardona W. Synthesis and
leishmanicidal activity of cinnamic acid esters:
structure–activity relationship. Med. Chem. Res.
(2014) 23: 1378-86.
De P, Baltas M and Bedos-Belval F. Cinnamic acid
derivatives as anticancer agents-a review. Curr. Med.
Chem. (2011) 18:1672-1703.
Liao HF, Chen YY, Liu JJ, Hsu ML, Shieh HJ, Liao
HJ, Shieh CJ, Shiao MS and Chen YJ. Inhibitory effect
of caffeic acid phenethyl ester on angiogenesis, tumor
invasion, and metastasis. J. Agric. Food Chem. (2003)
51:7907-7912.
Xie J, Yang F, Zhang M, Lam C, Qiao Y, Xiao J, Zhang
D, Ge Y, Fu L and Xie D. Antiproliferative activity
and SARs of caffeic acid esters with mono-substituted
phenylethanols moiety. Bioorg. Med. Chem. Lett.
(2017) 27: 131–4.
Borrelli F, Izzo AA, Di Carlo G, Maffia P, Russo A,
Maiello FM, Capasso F and Mascolo N. Effect of a
propolis extract and caffeic acid phenethyl ester on
formation of aberrant crypt foci and tumors in the rat
colon. Fitoterapia (2002) Suppl. 1 73: S38–S43.
Rao CV, Desai D, Kaul B and Amin S, Reddy BS.
Effect of caffeic acid esters on carcinogen-induced
mutagenicity and human colon adenocarcinoma cell
growth. Chem. Biol. Interact. (1992) 84:277-290.
Zhou W, Li HB, Xia CN, Zheng XM and Hu WX. The
synthesis and biological evaluation of some caffeic
acid amide derivatives: E-2-cyano-(3-substituted
phenyl)acrylamides. Bioorg. Med. Chem. Lett. (2009)
19:1861-1865.
Hung MW, Shiao MS, Tsai LC, Chang GG and Chang
TC. Apoptotic effect of caffeic acid phenethyl ester
and its ester and amide analogues in human cervical
cancer ME180 cells. Anticancer Res. (2003) 23: 4773-
80.
Gupta A, Saha P, Descôteaux C, Leblanc V, Asselin
E and Bérubé G. Design, synthesis and biological
evaluation of estradiol-chlorambucil hybrids as
anticancer agents. Bioor. Med. Chem. Lett. (2010) 20:
1614-8
Provencher-Mandeville J, Descôteaux C, Mandal
SK, Leblanc V, Asselin E and Bérubé G. Synthesis
of 17beta-estradiol-platinum(II) hybrid molecules
showing cytotoxic activity on breast cancer cell lines.
Bioor. Med. Chem. Lett. (2008) 18: 2282–7
Herrera-R A, Castrillón W, Otero E, Ruiz E, Carda M,
Agut R, Naranjo T, Moreno G, Maldonado ME and
Cardona-G W. Synthesis and antiproliferative activity
of 3- and 7-styrylcoumarins. Med. Chem. Res. (2018)
27: 1893-905
Pérez JM, Maldonado ME, Rojano B, Alzate F,
Sáez J and Cardona W. Comparative Antioxidant,
Antiproliferative and Apoptotic Effects of Ilex laurina
and Ilex paraguariensis on Colon Cancer Cells. Trop.
J. Pharm. Res. (2014) 13: 1279-86
García-Gutiérrez N, Maldonado-Celis ME, RojasLópez M, Loarca-Piña GF and Campos-Vega R. The
fermented non-digestible fraction of spent coffee
grounds induces apoptosis in human colon cancer cells
(SW480). J. Funct. Foods (2017) 30: 237-46
Nicoletti I, Migliorati G, Pagliacci MC, Grignani
F and Riccardi C. A rapid and simple method for
measuring thymocyte apoptosis by propidium iodide
staining and flow cytometry. J. Immunol. Methods
(1991) 139: 271-9
Goudreau N1, Brochu C, Cameron DR, Duceppe JS,
Faucher AM, Ferland JM, Grand-Maître C, Poirier
M, Simoneau B and Tsantrizos YS. Potent inhibitors
of the hepatitis C virus NS3 protease: design and
synthesis of macrocyclic substrate-based beta-strand
mimics. J. Org. Chem. (2004) 69: 6185- 201
Grigg R and Armstrong P. X Y ZH systems as potential
1,3 - dipoles. Part 25. Intramolecular cycloadditon
reactions of pyridoxal imines of ε-alkenyl α-amino
esthers. A possible new approach to pyridoxal enzyme
inhibition. Tetrahedron (1989) 45: 7581–6
Touaibia M and Guay M. Natural Product Total
Synthesis in the Organic Laboratory: Total Synthesis
of Caffeic Acid Phenethyl Ester (CAPE), A Potent
5-Lipoxygenase Inhibitor from Honeybee Hives. J.
Chem. Edu. (2011) 88: 473–5
Kwak SY, Lee S, Yang JK and Lee YS. Antioxidative
activities of caffeoyl-proline dipeptides. Food Chem.
(2012) 130: 847–52
Bastos E, Ciscato L and Baader W. Microwave‐Assisted
Protection of Phenols as tert‐Butyldimethylsilyl
(TBDMS) Ethers Under Solvent‐Free Conditions.
Synth. Commun. (2005) 35:1501-9
Sartori G, Ballini R, Bigi F, Bosica G, Maggi R and
Righi P. Protection (and deprotection) of functional
groups in organic synthesis by heterogeneous catalysis.
Chem. Rev. (2004) 104: 199-250.
LeBlanc LM, Paré AF, Jean-François J, Hébert MJG,
Surette ME and Touaibia M. Synthesis and Antiradical/
Antioxidant Activities of Caffeic Acid Phenethyl Ester
and Its Related Propionic, Acetic, and Benzoic Acid
Analogues. Molecules (2012) 17: 14637-50
Patrick GL. An Introduction to Medicinal Chemistry,
fifth ed., Oxford University Press, (2013) 1-14
Aponte JC, Castillo D, Estevez Y, Gonzalez G, Arevalo
J, Hammond GB and Sauvain M. In-vitro and in-vivo
anti-Leishmania activity of polysubstituted synthetic
chalcones. Bioorg. Med. Chem. Lett. (2010) 20:100-
103
Brenzan MA, Nakamura CV, Dias Filho BP, Ueda-
(20)
(21)
(22)
(23)
(24)
(25)
(26)
(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34)
(35)
(36)
(37)
(38)
(39)
(40)
(41)
(42)
(43)
(44)
(45)
S-allyl Cysteine Ester as Potential Anticancer Agents
1789
Nakamura T, Young MC, Côrrea AG, Alvim J Jr,
dos Santos AO and Cortez DA. Structure-activity
relationship of (-) mammea A/BB derivatives against
Leishmania amazonensis. Biomed. Pharmacother.
(2008) 62: 651-8.
Otero E, García E, Palacios G, Yepes LM, Carda
M, Agut R, Vélez ID, Cardona WI and Robledo
SM. Triclosan-caffeic acid hybrids: Synthesis,
leishmanicidal, trypanocidal and cytotoxic activities.
Eur. J. Med. Chem. (2017) 141: 73-83
Rajan P, Vedernikova I, Cos P, Berghe DV, Augustyns
K and Haemers A. Synthesis and evaluation of caffeic
acid amides as antioxidants. Bioorg. Med. Chem. Lett.
(2001) 11: 215-57
Sithara T, Arun KB, Syama HP, Reshmitha TR and
Nisha P. Morin Inhibits Proliferation of SW480
Colorectal Cancer Cells by Inducing Apoptosis
Mediated by Reactive Oxygen Species Formation and
Uncoupling of Warburg Effect. Front. Pharmacol.
(2017) 8: 640
Maldonado-Celisa ME1, Roussia S, Foltzer-Jourdainne
C, Gossé F, Lobstein A, Habold C, Roessner A,
Schneider-Stock R and Raul F. Modulation by
polyamines of apoptotic pathways triggered by
procyanidins in human metastatic SW620 cells. Cell.
Mol. Life Sci. (2008) 65: 1425-34
Maldonado-Celis ME, Bousserouel S, Gossé F, Minker
C, Lobstein A and Raul F. Differential induction of
apoptosis by apple procyanidins in TRAIL-sensitive
human colon tumor cells and derived TRAIL-resistant
metastatic cells. J. Cancer Mol. (2009) 5: 21-30
Caldon CE, Sutherland RL and Musgrove E. Cell cycle
proteins in epithelial cell differentiation: implications
for breast cancer. Cell Cycle (2010) 9: 1918-28
Zhang K, Wu J, Wu X, Wang X, Wang Y, Zhou N,
Kuo ML, Liu X, Zhou B, Chang L, Ann D and Yen
Y. p53R2 inhibits the proliferation of human cancer
cells in association with cell-cycle arrest. Mol. Cancer
Ther. (2011) 10: 269-78
Brooke GN, Culley RL, Dart DA, Mann DJ, Gaughan
L, McCracken SR, Robson CN, Spencer-Dene B,
Gamble SC, Powell SM, Wait R, Waxman J, Walker
MM and Bevan CL. FUS/TLS is a novel mediator
of androgen-dependent cell-cycle progression and
prostate cancer growth. Cancer Res. (2011) 7: 914-24
Li B, Shi XB, Nori D, Chao CK, Chen AM, Valicenti
R and White Rde V. Down-regulation of microRNA
106b is involved in p21-mediated cell cycle arrest in
response to radiation in prostate cancer cells. Prostate
(2011) 71: 567-74
Lapenna S and Giordano A. Cell cycle kinases as
therapeutic targets for cancer. Nat. Rev. Drug Discov.
(2009) 8: 547-66
Malumbres M1 and Barbacid M. Cell cycle, CDKs
and cancer: a changing paradigm. Nat. Rev. Cancer
(2009) 9: 153-66
(46)
(47)
(48)
(49)
(50)
(51)
(52)
(53)
(54)
(55)
(56)