Design, Synthesis, and Biological Evaluation of Novel Thiazolyl Substituted Bis-pyrazole Oxime Derivatives with Potent Antitumor Activities by Selectively Inducing Apoptosis and ROS in Cancer Cells

Author(s): Biao Xiong, Shi Chen, Peng Zhu, Meiling Huang, Weijie Gao, Rui Zhu, Jianqiang Qian, Yanfu Peng, Yanan Zhang, Hong Dai*, Yong Ling*.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: A large number of pyrazole derivatives have different biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic and antiepileptic activity. Among them, pyrazole oximes have attracted much attention due to their potential pharmacological activities, particularly anticancer activities.

Objective: Our goal is to synthesize novel thiazolyl substituted bis-pyrazole oxime derivatives with potent antitumor activities by selectively inducing apoptosis and Reactive Oxygen Species (ROS) accumulation in cancer cells.

Methods: Eighteen bis-pyrazole oximes were synthesized by conjugating thiazolyl substituted pyrazoles with pyrazoxime. The target compounds were characterized by 1HNMR, 13C NMR, and HRMS, and screened for their antiproliferative activity against four cancer cells in MTT assay. The most potent compound was examined for its inhibitory effect and ROS accumulation in both cancer cells HCT116 and normal intestinal epithelial cells CCD841. Finally, the most potent compound was further evaluated for its apoptotic induction by flow cytometry analysis and immunoblot analysis of apoptosis-related proteins and DNA damage proteins.

Results: Most compounds displayed potent antiproliferative activity against four cancer cell lines in vitro, displaying potencies superior to 5-FU. In particular, the most potent compound 13l selectively inhibited proliferation of colorectal cancer HCT116 cells but not normal colon CCD841 cells. Furthermore, compound 13l also selectively promoted intracellular ROS accumulation in HCT116 which was involved in 13l inhibition of cancer cell proliferation and induction of cell apoptosis. Finally, compound 13l also dose-dependently induced cancer cell apoptosis by regulating apoptotic and DNA damage related proteins expressions.

Conclusion: Our synthetic bis-pyrazole oxime derivatives possess potent antitumor activities by selectively inducing apoptosis and ROS accumulation in cancer cells, which may hold great promise as therapeutic agents for the treatment of human cancers.

Keywords: Antitumor activities, Bis-pyrazole oxime derivatives, antiproliferative activity, selectivity, apoptosis, Reactive Oxygen Species (ROS).

[1]
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
[2]
Bray, F.; Ren, J.S.; Masuyer, E.; Ferlay, J. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int. J. Cancer, 2013, 132, 1133-1145.
[3]
Roos, A.; Ding, Z.; Loftus, J.C.; Tran, N.L. Molecular and microenvironmental determinants of Glioma stem-like cell survival and invasion. Front. Oncol., 2017, 7, 120.
[4]
Ahmed, M.; Moussa, M.; Goldberg, S.N. Synergy in cancer treatment between liposomal chemotherapeutics and thermal ablation. Chem. Phys. Lipids, 2012, 165, 424-437.
[5]
Wang, F.; Ni, H.; Sun, F.; Li, M.; Chen, L. Overexpression of lncRNA AFAP1-AS1 correlates with poor prognosis and promotes tumorigenesis in colorectal cancer. Biomed. Pharmacother., 2016, 81, 152-159.
[6]
Trabelsi, A.; Ali, A.B.; Yacoub-Abid, L.B.; Stita, W.; Mokni, M.; Korbi, S. Primary invasive micropapillary carcinoma of the colon: Case report and review of the literature. Pathologica, 2008, 100, 428-430.
[7]
Fearon, E.R.; Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell, 1990, 61, 759-767.
[8]
Lewis, D.F.; Jacobs, M.N.; Dickins, M. Compound lipophilicity for substrate binding to human P450s in drug metabolism. Drug Discov. Today, 2004, 9, 530-537.
[9]
Xu, L.; Qin, Y.; Huang, J.; Qin, J.; Gu, J.; Zhu, H.; Liu, H.; Cai, Y.; Wu, X.; Feng, J. Effect of rapamycin-induced tumor vessel thrombosis combined with docetaxel in non-small-cell lung cancer. Anticancer Drugs, 2013, 24, 406-414.
[10]
Bekhit, A.A.; Fahmy, H.T.; Rostom, S.A.; Baraka, A.M. Design and synthesis of some substituted 1H-pyrazolyl- thiazolo[4,5-d]pyrimidines as anti-inflammatory-antimicrobial Agents. ChemInform, 2003, 38, 27-36.
[11]
Venepally, V.; Reddy Jala, R.C. An insight into the biological activities of heterocyclic-fatty acid hybrid molecules. Eur. J. Med. Chem., 2017, 141, 113-137.
[12]
Zhao, Y.; Hui, J.; Zhu, L. Synthesis and bioevaluation of novel arylnaphthalene lignans as anticancer agents. Med. Chem. Res., 2013, 22, 2505-2510.
[13]
Zhao, X.; Tan, Q.; Zhang, Z.; Zhao, Y. 1,3,5-Triazine inhibitors of histone deacetylases: Synthesis and biological activity. Med. Chem. Res., 2014, 23, 5188-5196.
[14]
Yuan, J.W.; Wang, S.F.; Luo, Z.L.; Qiu, H.Y.; Wang, P.F.; Zhang, X.; Yang, Y.A.; Yin, Y.; Zhang, F.; Zhu, H.L. Synthesis and biological evaluation of compounds which contain pyrazole, thiazole and naphthalene ring as antitumor agents. Bioorg. Med. Chem. Lett., 2014, 24, 2324-2328.
[15]
Reddy, T.S.; Kulhari, H.; Reddy, V.G.; Bansal, V.; Kamal, A.; Shukla, R. Design, synthesis and biological evaluation of 1,3-diphenyl-1H-pyrazole derivatives containing benzimidazole skeleton as potential anticancer and apoptosis inducing agents. Eur. J. Med. Chem., 2015, 101, 790-805.
[16]
Christodoulou, M.S.; Fokialakis, N.; Nam, S.; Jove, R.; Skaltsounis, A.L.; Haroutounian, S.A. Synthesis and biological evaluation of novel pyrazole derivatives as potential antitumor agents. Med. Chem., 2012, 8, 779-788.
[17]
Farag, A.M.; Ali, K.A.; El-Debss, T.M.; Mayhoub, A.S.; Amr, A.G.; Abdel-Hafez, N.A.; Abdulla, M.M. Design, synthesis and structure-activity relationship study of novel pyrazole-based heterocycles as potential antitumor agents. Eur. J. Med. Chem., 2010, 45, 5887-5898.
[18]
Insuasty, B.; Tigreros, A.; Orozco, F.; Quiroga, J.; Abonía, R.; Nogueras, M.; Sanchez, A.; Cobo, J. Synthesis of novel pyrazolic analogues of chalcones and their 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)- 1-phenyl-1H- pyrazole derivatives as potential antitumor agents. Bioorg. Med. Chem., 2010, 18, 4965-4974.
[19]
Farag, A.M.; Mayhoub, A.S.; Eldebss, T.M.; Amr, A.G.; Ali, K.A.; Abdel-Hafez, N.A.; Abdulla, M.M. Synthesis and structure-activity relationship studies of pyrazole-based heterocycles as antitumor agents. Arch. Pharm., 2010, 343, 384-396.
[20]
Knorr, L. Action of ethyl acetoacetate on hydrazine-quinizine derivatives. Chem. Ber., 1883, 17, 546-552.
[21]
Keter, F.K.; Darkwa, J. Perspective: The potential of pyrazole-based compounds in medicine. Biol. Met., 2012, 25, 9-21.
[22]
Küçükgüzel, Ş.G.; Şenkardeş, S. Recent advances in bioactive pyrazoles. Eur. J. Med. Chem., 2015, 97, 786-815.
[23]
Li, J.F.; Jin, H.J.; Zhou, H.Y.; Rothfussa, J.; Tu, Z.D. Synthesis and biological evaluation of pyrazole group-containing analogues for PDE10A. MedChemComm, 2013, 4, 443-449.
[24]
Park, H.J.; Lee, K.; Park, S.J.; Ahn, B.; Lee, J.C.; Cho, H.; Lee, K.I. Identification of antitumor activity of pyrazole oxime ethers. Bioorg. Med. Chem. Lett., 2005, 15, 3307-3312.
[25]
Zheng, L.W.; Li, Y.; Ge, D.; Zhao, B.X.; Liu, Y.R.; Lv, H.S.; Ding, J.; Miao, J.Y. Synthesis of novel oxime-containing pyrazole derivatives and discovery of regulators for apoptosis and autophagy in A549 lung cancer cells. Bioorg. Med. Chem. Lett., 2010, 20, 4766-4770.
[26]
Dai, H.; Ge, S.; Li, G.; Chen, J.; Shi, Y.; Ye, L.; Ling, Y. Synthesis and bioactivities of novel pyrazole oxime derivatives containing a 1,2,3-thiadiazole moiety. Bioorg. Med. Chem. Lett., 2016, 26, 4504-4507.
[27]
Dai, H.; Ge, S.; Guo, J.; Chen, S.; Huang, M.; Yang, J.; Sun, S.; Ling, Y.; Shi, Y. Development of novel bis-pyrazole derivatives as antitumor agents with potent apoptosis induction effects and DNA damage. Eur. J. Med. Chem., 2018, 143, 1066-1076.
[28]
Keter, F.K.; Kanyanda, S.; Lyantagaye, S.S.; Darkwa, J.; Rees, D.J.; Meyer, M. Evaluation of dichloro-bis(pyrazole)palladium(II) and dichloro-bis(pyrazole)platinum(II) complexes as anticancer agents. Cancer Chemother. Pharmacol., 2008, 63, 127-138.
[29]
Gomha, S.M.; Edrees, M.M.; Altalbawy, F.M. Synthesis and characterization of some new bis- pyrazolyl-thiazoles incorporating the thiophene moiety as potent anti-tumor agents. Int. J. Mol. Sci., 2016, 17E1499
[30]
Zhao, M.Y.; Yin, Y.; Yu, X.W.; Sangani, C.B.; Wang, S.F.; Lu, A.M.; Yang, L.F.; Lv, P.C.; Jiang, M.G.; Zhu, H.L. Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1H-pyrazole thiazole derivatives as BRAF(V600E) inhibitors. Bioorg. Med. Chem., 2015, 23, 46-54.
[31]
Zou, Z.; Chang, H.; Li, H.; Wang, S. Induction of reactive oxygen species: An emerging approach for cancer therapy. Apoptosis, 2017, 22, 1321-1335.
[32]
Lu, Y.; Zhang, R.; Liu, S.; Zhao, Y.; Gao, J. ZT-25, a new vacuolar H(+)-ATPase inhibitor, induces apoptosis and protective autophagy through ROS generation in HepG2 cells. Eur. J. Pharmacol., 2016, 771, 130-138.
[33]
Zafarullah, M.; Li, W.Q.; Sylvester, J.; Ahmad, M. Molecular mechanisms of N-acetylcysteine actions. Cell. Mol. Life Sci., 2003, 60, 6-20.
[34]
Sha, M.; Ye, J.; Zhang, L.X.; Luan, Z.Y.; Chen, Y. Celastrol induces apoptosis of gastric cancer cells by miR-21 inhibiting PI3K/Akt-NF-κB signaling pathway. Pharmacology, 2014, 93, 39-46.
[35]
Wang, F.; Ma, H.X.; Liu, Z.G.; Huang, W.; Xu, X.J. α-Mangostin inhibits DMBA/TPA-induced skin cancer through inhibiting inflammation and promoting autophagy and apoptosis by regulating PI3K/Akt/mTOR signaling pathway in mice. Biomed. Pharmacother., 2017, 92, 672-680.
[36]
Harada, T.; Harada, K.; Ueyama, Y. The enhancement of tumor radioresponse by combined treatment with cepharanthine is accompanied by the inhibition of DNA damage repair and the induction of apoptosis in oral squamous cell carcinoma. Int. J. Oncol., 2012, 41, 565-572.
[37]
Dai, H.; Li, G.; Chen, J.; Shi, Y.; Ge, S.; Fan, C.; He, H. Synthesis and biological activities of novel 1,3,4-thiadiazole-containing pyrazole oxime derivatives. Bioorg. Med. Chem. Lett., 2016, 26, 3818-3821.
[38]
Ling, Y.; Xu, C.; Luo, L.; Cao, J.; Feng, J.; Xue, Y.; Zhu, Q.; Ju, C.; Li, F.; Zhang, Y.; Zhang, Y.; Ling, X. Novel β-Carboline/Hydroxamic acid hybrids targeting both histone deacetylase and DNA display high anticancer activity regulation of the P53 signaling pathway. J. Med. Chem., 2015, 58, 9214-9227.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 7
Year: 2019
Page: [743 - 754]
Pages: 12
DOI: 10.2174/1573406414666180827112724
Price: $65

Article Metrics

PDF: 33
HTML: 2