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


Citar

Texto integral

Resumo

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.

Sobre autores

Yunfeng Zhang

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine

Email: info@benthamscience.net

Jiale Ma

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine

Email: info@benthamscience.net

Yujie Pei

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine

Email: info@benthamscience.net

Zeyuan Xie

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine

Email: info@benthamscience.net

Dong-Jun Fu

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine

Autor responsável pela correspondência
Email: info@benthamscience.net

Jun Li

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine

Autor responsável pela correspondência
Email: info@benthamscience.net

Bibliografia

  1. Siegel, R.L.; Miller, K.D.; Wagle, N.S. Jemal ahmedin. Cancer statistics. CA Cancer J. Clin., 2023, 73, 17-48. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1021/acs.jnatprod.9b01285 PMID: 32162523
  8. Hengartner, M.O. The biochemistry of apoptosis. Nature, 2000, 407(6805), 770-776. doi: 10.1038/35037710 PMID: 11048727
  9. Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol., 2007, 35(4), 495-516. doi: 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. doi: 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. doi: 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. doi: 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 pyrrolo1,2-aimidazoles as WDR5 WIN-site inhibitors using fragment-based methods and structure-based design. J. Med. Chem., 2018, 61(13), 5623-5642. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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-dihydropyrano2,3- fchromen-4(8 H)-one based hybrids as potential mitochondrial apoptosis inducers. Eur. J. Med. Chem., 2016, 122, 302-318. doi: 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. doi: 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-sulfanylenebenzod 1,3,2 oxazaphospholes with improved antiproliferative activity. J. Med. Chem., 2015, 58(16), 6456-6480. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1038/s41422-019-0164-5 PMID: 30948788
  34. Danial, N.N.; Korsmeyer, S. J. Cell Death. Cell, 2004, 116(2), 205-219. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1016/j.jcis.2014.12.092 PMID: 25622047

Arquivos suplementares

Arquivos suplementares
Ação
1. JATS XML
Baixar

Declaração de direitos autorais © Bentham Science Publishers, 2023