Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis of S-2-phenylchromane Derivatives and Evaluation of the Antiproliferative Properties as Apoptosis Inducers in Cancer Cell Lines

Author(s): Yunfeng Zhang, Jiale Ma, Yujie Pei, Zeyuan Xie, Dong-Jun Fu* and Jun Li*

Volume 23, Issue 16, 2023

Published on: 10 May, 2023

Page: [1848 - 1859] Pages: 12

DOI: 10.2174/1871520623666230420100254

Price: $65

Abstract

Background: Cancer remains one of the major health issues globally, where chemotherapy forms the main treatment mode for different types of cancers. Due to cancer cell ability to develop resistance, decreased clinical effectiveness of anticancer drugs can occur. Therefore, the need to synthesize novel antitumor drugs remains important.

Objective: The aim of our work consisted of synthesizing S-2-phenylchromane derivatives containing the tertiary amide or 1,2,3-triazole fragments with promising anticancer activity.

Methods: A series of S-2-phenylchromane derivatives were synthesized and evaluated for cytotoxic activity against three selected cancer cell lines (HGC-27 human gastric carcinoma cell line, Huh-7 epithelial-like tumorigenic cells, and A549 adenocarcinomic human alveolar basal epithelial cells) using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. Hoechst staining was used to detect the effects of S-2-phenylchromane derivatives on apoptosis. The apoptosis percentages were detected by annexin V-fluoresceine isothiocyanate/propidium iodide (Annexin V-FITC/PI) double staining assay with flow cytometry. Expression levels of apoptosis-related proteins were detected by western blot.

Results: Cell line A549, consisting of adenocarcinomic human alveolar basal epithelial cells, displayed the highest sensitivity to the S-2-phenylchromane derivatives. Among these compounds, E2 showed the most potent antiproliferative activity against A549 cells with an IC50 value of 5.60 μM. Hoechst staining and flow cytometry analysis revealed apoptosis in A549 cells by compound E2. In addition, activation of the expression levels of caspase-3, caspase-7, and their substrate poly (ADP-ribose) polymerase (PARP) by E2 was detected by western blot.

Conclusion: In summary, results point towards compound E2, an S-2-phenylchromane derivative, as a potential lead molecule in anticancer agents for human adenocarcinomic alveolar basal cells based on the induction of apoptosis.

« Previous Next »
Graphical Abstract

[1]
Siegel, R.L.; Miller, K.D.; Wagle, N.S. Jemal ahmedin. Cancer statistics. CA Cancer J. Clin., 2023, 73, 17-48.
[http://dx.doi.org/10.3322/caac.21763] [PMID: 36633525]
[2]
Gao, L.; Wu, Z.X.; Assaraf, Y.G.; Chen, Z.S.; Wang, L. Overcoming anti-cancer drug resistance via restoration of tumor suppressor gene function. Drug Resist. Updat., 2021, 57, 100770.
[http://dx.doi.org/10.1016/j.drup.2021.100770] [PMID: 34175687]
[3]
Horinaka, M.; Yoshida, T.; Nakata, S.; Shiraishi, T.; Tomosugi, M.; Yoshikawa, S.; Wakada, M.; Sakai, T. Aclarubicin enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis through death receptor 5 upregulation. Cancer Sci., 2012, 103(2), 282-287.
[http://dx.doi.org/10.1111/j.1349-7006.2011.02150.x] [PMID: 22077238]
[4]
Cao, W.; Liu, Y.; Zhang, R.; Zhang, B.; Wang, T.; Zhu, X.; Mei, L.; Chen, H.; Zhang, H.; Ming, P.; Huang, L. Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells. Sci. Rep., 2015, 5(1), 8477.
[http://dx.doi.org/10.1038/srep08477] [PMID: 26166037]
[5]
Jeong, M.S.; Lee, K.W.; Choi, Y.J.; Kim, Y.G.; Hwang, H.H.; Lee, S.Y.; Jung, S.E.; Park, S.A.; Lee, J.H.; Joo, Y.J.; Cho, S.G.; Ko, S.G. Synergistic antitumor activity of SH003 and docetaxel via EGFR signaling inhibition in non-small cell lung cancer. Int. J. Mol. Sci., 2021, 22(16), 8405.
[http://dx.doi.org/10.3390/ijms22168405] [PMID: 34445110]
[6]
Quoix, E.; Breton, J.L.; Daniel, C.; Jacoulet, P.; Debieuvre, D.; Paillot, N.; Kessler, R.; Moreau, L.; Coëtmeur, D.; Lemarié, E.; Milleron, B. Etoposide phosphate with carboplatin in the treatment of elderly patients with small-cell lung cancer: A phase II study. Ann. Oncol., 2001, 12(7), 957-962.
[http://dx.doi.org/10.1023/A:1011171722175] [PMID: 11521802]
[7]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod., 2020, 83(3), 770-803.
[http://dx.doi.org/10.1021/acs.jnatprod.9b01285] [PMID: 32162523]
[8]
Hengartner, M.O. The biochemistry of apoptosis. Nature, 2000, 407(6805), 770-776.
[http://dx.doi.org/10.1038/35037710] [PMID: 11048727]
[9]
Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol., 2007, 35(4), 495-516.
[http://dx.doi.org/10.1080/01926230701320337] [PMID: 17562483]
[10]
Kasibhatla, S.; Tseng, B. Why target apoptosis in cancer treatment? Mol. Cancer Ther., 2003, 2(6), 573-580.
[PMID: 12813137]
[11]
Su, X.Q.; Song, Y.L.; Zhang, J.; Huo, H.X.; Huang, Z.; Zheng, J.; Zhang, Q.; Zhao, Y.F.; Xiao, W.; Li, J.; Tu, P.F. Dihydrochalcones and homoisoflavanes from the red resin of Dracaena cochinchinensis (Chinese dragon’s blood). Fitoterapia, 2014, 99, 64-71.
[http://dx.doi.org/10.1016/j.fitote.2014.09.006] [PMID: 25218969]
[12]
Chen, X.; Zhao, Y.; Yang, A.; Tian, Y.; Pang, D.; Sun, J.; Tang, L.; Huang, H.; Wang, Y.; Zhao, Y.; Tu, P.; Hu, Z.; Li, J. Chinese dragon’s blood EtOAc extract inhibits liver cancer growth through downregulation of Smad3. Front. Pharmacol., 2020, 11, 669.
[http://dx.doi.org/10.3389/fphar.2020.00669] [PMID: 32477135]
[13]
Liu, J.; Mei, W.L.; Wu, J.; Zhao, Y.X.; Peng, M.; Dai, H.F. A new cytotoxic homoisoflavonoid from Dracaena cambodiana. J. Asian Nat. Prod. Res., 2009, 11(2), 192-195.
[http://dx.doi.org/10.1080/10286020802674962] [PMID: 19219735]
[14]
Wang, F.; Jeon, K.O.; Salovich, J.M.; Macdonald, J.D.; Alvarado, J.; Gogliotti, R.D.; Phan, J.; Olejniczak, E.T.; Sun, Q.; Wang, S.; Camper, D.; Yuh, J.P.; Shaw, J.G.; Sai, J.; Rossanese, O.W.; Tansey, W.P.; Stauffer, S.R.; Fesik, S.W. Discovery of potent 2-aryl-6,7-dihydro-5H pyrrolo[1,2-a]imidazoles as WDR5 WIN-site inhibitors using fragment-based methods and structure-based design. J. Med. Chem., 2018, 61(13), 5623-5642.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00375] [PMID: 29889518]
[15]
ElHady, A.K.; Abdel-Halim, M.; Abadi, A.H.; Engel, M. Development of selective clk1 and -4 inhibitors for cellular depletion of cancer-relevant proteins. J. Med. Chem., 2017, 60(13), 5377-5391.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01915] [PMID: 28561591]
[16]
Hammill, J.T.; Scott, D.C.; Min, J.; Connelly, M.C.; Holbrook, G.; Zhu, F.; Matheny, A.; Yang, L.; Singh, B.; Schulman, B.A.; Guy, R.K. Piperidinyl ureas chemically control defective in Cullin Neddylation 1 (DCN1)-mediated Cullin Neddylation. J. Med. Chem., 2018, 61(7), 2680-2693.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01277] [PMID: 29547696]
[17]
Fu, D.J.; Song, J.; Zhu, T.; Pang, X.J.; Wang, S.H.; Zhang, Y.B.; Wu, B.W.; Wang, J.W.; Zi, X.; Zhang, S.Y.; Liu, H.M. Discovery of novel tertiary amide derivatives as NEDDylation pathway activators to inhibit the tumor progression in vitro and in vivo. Eur. J. Med. Chem., 2020, 192, 112153.
[http://dx.doi.org/10.1016/j.ejmech.2020.112153] [PMID: 32135407]
[18]
Fu, D.J.; Cui, X.X.; Zhu, T.; Zhang, Y.B.; Hu, Y.Y.; Zhang, L.R.; Wang, S.H.; Zhang, S.Y. Discovery of novel indole derivatives that inhibit NEDDylation and MAPK pathways against gastric cancer MGC803 cells. Bioorg. Chem., 2021, 107, 104634.
[http://dx.doi.org/10.1016/j.bioorg.2021.104634] [PMID: 33476867]
[19]
Fu, D.J.; Li, P.; Wu, B.W.; Cui, X.X.; Zhao, C.B.; Zhang, S.Y. Molecular diversity of trimethoxyphenyl-1,2,3-triazole hybrids as novel colchicine site tubulin polymerization inhibitors. Eur. J. Med. Chem., 2019, 165, 309-322.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.033] [PMID: 30690300]
[20]
Majeed, R.; Sangwan, P.L.; Chinthakindi, P.K.; Khan, I.; Dangroo, N.A.; Thota, N.; Hamid, A.; Sharma, P.R.; Saxena, A.K.; Koul, S. Synthesis of 3-O-propargylated betulinic acid and its 1,2,3-triazoles as potential apoptotic agents. Eur. J. Med. Chem., 2013, 63, 782-792.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.028] [PMID: 23584541]
[21]
Duan, Y.C.; Zheng, Y.C.; Li, X.C.; Wang, M.M.; Ye, X.W.; Guan, Y.Y.; Liu, G.Z.; Zheng, J.X.; Liu, H.M. Design, synthesis and antiproliferative activity studies of novel 1,2,3-triazole–dithiocarbamate–urea hybrids. Eur. J. Med. Chem., 2013, 64, 99-110.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.058] [PMID: 23644193]
[22]
Stefely, J.A.; Palchaudhuri, R.; Miller, P.A.; Peterson, R.J.; Moraski, G.C.; Hergenrother, P.J.; Miller, M.J. N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide as a new scaffold that provides rapid access to antimicrotubule agents: Synthesis and evaluation of antiproliferative activity against select cancer cell lines. J. Med. Chem., 2010, 53(8), 3389-3395.
[http://dx.doi.org/10.1021/jm1000979] [PMID: 20334421]
[23]
Dheer, D.; Singh, V.; Shankar, R. Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg. Chem., 2017, 71, 30-54.
[http://dx.doi.org/10.1016/j.bioorg.2017.01.010] [PMID: 28126288]
[24]
Li, S.; Li, X.; Zhang, T.; Kamara, M.O.; Liang, J.; Zhu, J.; Meng, F. Design, synthesis and biological evaluation of homoerythrina alkaloid derivatives bearing a triazole moiety as PARP-1 inhibitors and as potential antitumor drugs. Bioorg. Chem., 2020, 94, 103385.
[http://dx.doi.org/10.1016/j.bioorg.2019.103385] [PMID: 31669094]
[25]
Alam, M.M.; Malebari, A.M.; Syed, N.; Neamatallah, T.; Almalki, A.S.A.; Elhenawy, A.A.; Obaid, R.J.; Alsharif, M.A. Design, synthesis and molecular docking studies of thymol based 1,2,3-triazole hybrids as thymidylate synthase inhibitors and apoptosis inducers against breast cancer cells. Bioorg. Med. Chem., 2021, 38, 116136.
[http://dx.doi.org/10.1016/j.bmc.2021.116136] [PMID: 33894490]
[26]
Wei, G.; Luan, W.; Wang, S.; Cui, S.; Li, F.; Liu, Y.; Liu, Y.; Cheng, M. A library of 1,2,3-triazole-substituted oleanolic acid derivatives as anticancer agents: Design, synthesis, and biological evaluation. Org. Biomol. Chem., 2015, 13(5), 1507-1514.
[http://dx.doi.org/10.1039/C4OB01605J] [PMID: 25476168]
[27]
Sakthivel, P.; Ilangovan, A.; Kaushik, M.P. Natural product-inspired rational design, synthesis and biological evaluation of 2,3-dihydropyrano[2,3- f]chromen-4(8 H)-one based hybrids as potential mitochondrial apoptosis inducers. Eur. J. Med. Chem., 2016, 122, 302-318.
[http://dx.doi.org/10.1016/j.ejmech.2016.06.044] [PMID: 27376493]
[28]
Sharma, P.; Srinivasa Reddy, T.; Thummuri, D.; Senwar, K.R.; Praveen Kumar, N.; Naidu, V.G.M.; Bhargava, S.K.; Shankaraiah, N. Synthesis and biological evaluation of new benzimidazole-thiazolidinedione hybrids as potential cytotoxic and apoptosis inducing agents. Eur. J. Med. Chem., 2016, 124, 608-621.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.029] [PMID: 27614408]
[29]
Feng, W.; Teo, X.Y.; Novera, W.; Ramanujulu, P.M.; Liang, D.; Huang, D.; Moore, P.K.; Deng, L.W.; Dymock, B.W. Discovery of new H2S releasing phosphordithioates and 2,3-dihydro-2-phenyl-2-sulfanylenebenzo[d] [1,3,2] oxazaphospholes with improved antiproliferative activity. J. Med. Chem., 2015, 58(16), 6456-6480.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00848] [PMID: 26147240]
[30]
Walsh, J.G.; Cullen, S.P.; Sheridan, C.; Lüthi, A.U.; Gerner, C.; Martin, S.J. Executioner caspase-3 and caspase-7 are functionally distinct proteases. Proc. Natl. Acad. Sci. USA, 2008, 105(35), 12815-12819.
[http://dx.doi.org/10.1073/pnas.0707715105] [PMID: 18723680]
[31]
Brentnall, M.; Rodriguez-Menocal, L.; De Guevara, R.L.; Cepero, E.; Boise, L.H. Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol., 2013, 14(1), 32.
[http://dx.doi.org/10.1186/1471-2121-14-32] [PMID: 23834359]
[32]
Huang, W.T.; Liu, J.; Liu, J.F.; Hui, L.; Ding, Y.L.; Chen, S.W. Synthesis and biological evaluation of conjugates of deoxypodophyllotoxin and 5-FU as inducer of caspase-3 and -7. Eur. J. Med. Chem., 2012, 49, 48-54.
[http://dx.doi.org/10.1016/j.ejmech.2011.12.005] [PMID: 22244588]
[33]
Tang, D.; Kang, R.; Berghe, T.V.; Vandenabeele, P.; Kroemer, G. The molecular machinery of regulated cell death. Cell Res., 2019, 29(5), 347-364.
[http://dx.doi.org/10.1038/s41422-019-0164-5] [PMID: 30948788]
[34]
Danial, N.N.; Korsmeyer, S. J. Cell Death. Cell, 2004, 116(2), 205-219.
[http://dx.doi.org/10.1016/S0092-8674(04)00046-7] [PMID: 14744432]
[35]
D’Amours, D.; Sallmann, F.R.; Dixit, V.M.; Poirier, G.G. Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: Implications for apoptosis. J. Cell Sci., 2001, 114(20), 3771-3778.
[http://dx.doi.org/10.1242/jcs.114.20.3771] [PMID: 11707529]
[36]
Espino, J.; Fernández-Delgado, E.; Estirado, S.; de la Cruz-Martinez, F.; Villa-Carballar, S.; Viñuelas-Zahínos, E.; Luna-Giles, F.; Pariente, J.A. Synthesis and structure of a new thiazoline-based palladium(II) complex that promotes cytotoxicity and apoptosis of human promyelocytic leukemia HL-60 cells. Sci. Rep., 2020, 10(1), 16745.
[http://dx.doi.org/10.1038/s41598-020-73488-0] [PMID: 33028870]
[37]
Estirado, S.; Fernández-Delgado, E.; Viñuelas-Zahínos, E.; Luna-Giles, F.; Rodríguez, A.B.; Pariente, J.A.; Espino, J. Pro-apoptotic and anti-migration properties of a thiazoline-containing platinum (II) complex in MDA-MB-231 breast cancer cells: The role of melatonin as a synergistic agent. Antioxidants, 2022, 11(10), 1971.
[http://dx.doi.org/10.3390/antiox11101971] [PMID: 36290694]
[38]
Mangal, S.; Gao, W.; Li, T.; Zhou, Q. Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: Challenges and opportunities. Acta Pharmacol. Sin., 2017, 38(6), 782-797.
[http://dx.doi.org/10.1038/aps.2017.34] [PMID: 28504252]
[39]
Garrastazu Pereira, G.; Lawson, A.J.; Buttini, F.; Sonvico, F. Loco-regional administration of nanomedicines for the treatment of lung cancer. Drug Deliv., 2016, 23(8), 2881-2896.
[http://dx.doi.org/10.3109/10717544.2015.1114047] [PMID: 26585837]
[40]
Bailey, M.M.; Berkland, C.J. Nanoparticle formulations in pulmonary drug delivery. Med. Res. Rev., 2009, 29(1), 196-212.
[http://dx.doi.org/10.1002/med.20140] [PMID: 18958847]
[41]
Gaspar, M.M.; Radomska, A.; Gobbo, O.L.; Bakowsky, U.; Radomski, M.W.; Ehrhardt, C. Targeted delivery of transferrin-conjugated liposomes to an orthotopic model of lung cancer in nude rats. J. Aerosol Med. Pulm. Drug Deliv., 2012, 25(6), 310-318.
[http://dx.doi.org/10.1089/jamp.2011.0928] [PMID: 22857016]
[42]
Hu, L.; Jia, Y. WenDing, Preparation and characterization of solid lipid nanoparticles loaded with epirubicin for pulmonary delivery. Pharmazie, 2010, 65(8), 585-587.
[PMID: 20824958]
[43]
Jyoti, K.; Kaur, K.; Pandey, R.S.; Jain, U.K.; Chandra, R.; Madan, J. Inhalable nanostructured lipid particles of 9-bromo-noscapine, a tubulin-binding cytotoxic agent: In vitro and in vivo studies. J. Colloid Interface Sci., 2015, 445, 219-230.
[http://dx.doi.org/10.1016/j.jcis.2014.12.092] [PMID: 25622047]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy