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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Design, Synthesis, and Biological Evaluation of 4-amino Substituted 2Hchromen- 2-one Derivatives as an NEDD8 Activating Enzyme Inhibitor in Pancreatic Cancer Cells

Author(s): Lijuan Zhu, Peng Lu, Lei Gong, Cheng Lu, Mengli Li and Yubin Wang*

Volume 16, Issue 7, 2020

Page: [969 - 983] Pages: 15

DOI: 10.2174/1573406416666191227121520

Price: $65

Abstract

Background: NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in carcinomas. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment.

Objective: In this article, we decided to study the synthesis and screening of 4-amino substituted 2H-chromen-2-one derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3.

Methods: After synthesis of twenty targeted compounds, we evaluated their anti-proliferative activity against six cancer cell lines, cytotoxicity against three normal cell lines through MTT assay, and hemolysis to screen out the candidate compound, which was further conducted drug-like physical property measurement, target confirmation by enzyme-based experiment, cell apoptosis, and synergistic effect research.

Results: Starting from intermediates 4 and 5, several new 4-amino substituted 2H-chromen-2-one derivatives (9-28) were synthesized and evaluated for their cell activities using six cancer cell lines. We performed tests of cytotoxicity, hemolysis, ATP-dependent NAE inhibition in the enzyme- based system, apoptosis, and synergistic effect in BxPC-3 cells against the best candidate compound 21.

Conclusion: Based on these results, we found that compound 21 inhibited NAE activity in an ATP-dependent manner in the enzyme-based system, induced apoptosis in BxPC-3 cells, and synergized with bortezomib on BxPC-3 cell growth inhibition. Additionally, it had low toxicity with reasonable Log P-value and water solubility.

Keywords: Amino substitutes, 2H-chromen-2-one derivatives, NEDD8 activating enzyme inhibitor, pancreatic cancer, BxPC-3 cells, synthesis, biological evaluation.

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[1]
Ashktorab, H.; Kupfer, S.S.; Brim, H.; Carethers, J.M. Racial disparity in gastrointestinal cancer risk. Gastroenterology, 2017, 153(4), 910-923.
[http://dx.doi.org/10.1053/j.gastro.2017.08.018] [PMID: 28807841]
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[http://dx.doi.org/10.3322/caac.21442] [PMID: 29313949]
[3]
Chen, W.; Zheng, R.; Zhang, S.; Zeng, H.; Zuo, T.; Xia, C.; Yang, Z.; He, J. Cancer incidence and mortality in China in 2013: an analysis based on urbanization level. Chin. J. Cancer Res., 2017, 29(1), 1-10.
[http://dx.doi.org/10.21147/j.issn.1000-9604.2017.01.01] [PMID: 28373748]
[4]
Salman, B.; Zhou, D.; Jaffee, E.M.; Edil, B.H.; Zheng, L. Vaccine therapy for pancreatic cancer. OncoImmunology, 2013, 2(12)e26662
[http://dx.doi.org/10.4161/onci.26662] [PMID: 24498551]
[5]
Burris, H.A., III; Moore, M.J.; Andersen, J.; Green, M.R.; Rothenberg, M.L.; Modiano, M.R.; Cripps, M.C.; Portenoy, R.K.; Storniolo, A.M.; Tarassoff, P.; Nelson, R.; Dorr, F.A.; Stephens, C.D.; Von Hoff, D.D. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol., 1997, 15(6), 2403-2413.
[http://dx.doi.org/10.1200/JCO.1997.15.6.2403] [PMID: 9196156]
[6]
Bobrov, E.; Skobeleva, N.; Restifo, D.; Beglyarova, N.; Cai, K.Q.; Handorf, E.; Campbell, K.; Proia, D.A.; Khazak, V.; Golemis, E.A.; Astsaturov, I. Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models. Oncotarget, 2017, 8(3), 4399-4409.
[http://dx.doi.org/10.18632/oncotarget.12642] [PMID: 27779106]
[7]
Dubey, R.D.; Alam, N.; Saneja, A.; Khare, V.; Kumar, A.; Vaidh, S.; Mahajan, G.; Sharma, P.R.; Singh, S.K.; Mondhe, D.M.; Gupta, P.N. Development and evaluation of folate functionalized albumin nanoparticles for targeted delivery of gemcitabine. Int. J. Pharm., 2015, 492(1-2), 80-91.
[http://dx.doi.org/10.1016/j.ijpharm.2015.07.012] [PMID: 26165611]
[8]
Khare, V.; Alam, N.; Saneja, A.; Dubey, R.D.; Gupta, P.N. Targeted drug delivery systems for pancreatic cancer. J. Biomed. Nanotechnol., 2014, 10(12), 3462-3482.
[http://dx.doi.org/10.1166/jbn.2014.2036] [PMID: 26000366]
[9]
Khare, V.; Singh, A.; Mahajan, G.; Alam, N.; Kour, S.; Gupta, M.; Kumar, A.; Singh, G.; Singh, S.K.; Saxena, A.K.; Mondhe, D.M.; Gupta, P.N. Long-circulatory nanoparticles for gemcitabine delivery: Development and investigation of pharmacokinetics and in-vivo anticancer efficacy. Eur. J. Pharm. Sci., 2016, 92, 183-193.
[http://dx.doi.org/10.1016/j.ejps.2016.07.007] [PMID: 27404580]
[10]
Parsian, M.; Unsoy, G.; Mutlu, P.; Yalcin, S.; Tezcaner, A.; Gunduz, U. Loading of Gemcitabine on chitosan magnetic nanoparticles increases the anti-cancer efficacy of the drug. Eur. J. Pharmacol., 2016, 784, 121-128.
[http://dx.doi.org/10.1016/j.ejphar.2016.05.016] [PMID: 27181067]
[11]
Yang, F.; Jin, C.; Jiang, Y.; Li, J.; Di, Y.; Ni, Q.; Fu, D. Liposome based delivery systems in pancreatic cancer treatment: from bench to bedside. Cancer Treat. Rev., 2011, 37(8), 633-642.
[http://dx.doi.org/10.1016/j.ctrv.2011.01.006] [PMID: 21330062]
[12]
Yoshida, M.; Takimoto, R.; Murase, K.; Sato, Y.; Hirakawa, M.; Tamura, F.; Sato, T.; Iyama, S.; Osuga, T.; Miyanishi, K.; Takada, K.; Hayashi, T.; Kobune, M.; Kato, J. Targeting anticancer drug delivery to pancreatic cancer cells using a fucose-bound nanoparticle approach. PLoS One, 2012, 7(7)e39545
[http://dx.doi.org/10.1371/journal.pone.0039545] [PMID: 22808043]
[13]
Haglund, K.; Dikic, I. The role of ubiquitylation in receptor endocytosis and endosomal sorting. J. Cell Sci., 2012, 125(Pt 2), 265-275.
[http://dx.doi.org/10.1242/jcs.091280] [PMID: 22357968]
[14]
Ruggiano, A.; Foresti, O.; Carvalho, P. Quality control: ER-associated degradation: protein quality control and beyond. J. Cell Biol., 2014, 204(6), 869-879.
[http://dx.doi.org/10.1083/jcb.201312042] [PMID: 24637321]
[15]
Trotman, L.C.; Wang, X.; Alimonti, A.; Chen, Z.; Teruya-Feldstein, J.; Yang, H.; Pavletich, N.P.; Carver, B.S.; Cordon-Cardo, C.; Erdjument-Bromage, H.; Tempst, P.; Chi, S.G.; Kim, H.J.; Misteli, T.; Jiang, X.; Pandolfi, P.P. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell, 2007, 128(1), 141-156.
[http://dx.doi.org/10.1016/j.cell.2006.11.040] [PMID: 17218261]
[16]
Buckley, D.L.; Crews, C.M. Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system. Angew. Chem. Int. Ed. Engl., 2014, 53(9), 2312-2330.
[http://dx.doi.org/10.1002/anie.201307761] [PMID: 24459094]
[17]
da Silva, S.R.; Paiva, S.L.; Lukkarila, J.L.; Gunning, P.T. Exploring a new frontier in cancer treatment: targeting the ubiquitin and ubiquitin-like activating enzymes. J. Med. Chem., 2013, 56(6), 2165-2177.
[http://dx.doi.org/10.1021/jm301420b] [PMID: 23360215]
[18]
Hershko, A. The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ., 2005, 12(9), 1191-1197.
[http://dx.doi.org/10.1038/sj.cdd.4401702] [PMID: 16094395]
[19]
Bedford, L.; Lowe, J.; Dick, L.R.; Mayer, R.J.; Brownell, J.E. Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat. Rev. Drug Discov., 2011, 10(1), 29-46.
[http://dx.doi.org/10.1038/nrd3321] [PMID: 21151032]
[20]
Ferdoush, J.; Karmakar, S.; Barman, P.; Kaja, A.; Uprety, B.; Batra, S.K.; Bhaumik, S.R. Ubiquitin−proteasome system regulation of an evolutionarily conserved RNA polymerase II-associated factor 1 involved in pancreatic oncogenesis. Biochemistry, 2017, 56(46), 6083-6086.
[http://dx.doi.org/10.1021/acs.biochem.7b00865] [PMID: 29023102]
[21]
Nakayama, K.; Qi, J.; Ronai, Z. The ubiquitin ligase Siah2 and the hypoxia response. Mol. Cancer Res., 2009, 7(4), 443-451.
[http://dx.doi.org/10.1158/1541-7786.MCR-08-0458] [PMID: 19372575]
[22]
Zhang, Q.; Meng, Y.; Zhang, L.; Chen, J.; Zhu, D. RNF13: a novel RING-type ubiquitin ligase over-expressed in pancreatic cancer. Cell Res., 2009, 19(3), 348-357.
[http://dx.doi.org/10.1038/cr.2008.285] [PMID: 18794910]
[23]
Soucy, T.A.; Smith, P.G.; Milhollen, M.A.; Berger, A.J.; Gavin, J.M.; Adhikari, S.; Brownell, J.E.; Burke, K.E.; Cardin, D.P.; Critchley, S.; Cullis, C.A.; Doucette, A.; Garnsey, J.J.; Gaulin, J.L.; Gershman, R.E.; Lublinsky, A.R.; McDonald, A.; Mizutani, H.; Narayanan, U.; Olhava, E.J.; Peluso, S.; Rezaei, M.; Sintchak, M.D.; Talreja, T.; Thomas, M.P.; Traore, T.; Vyskocil, S.; Weatherhead, G.S.; Yu, J.; Zhang, J.; Dick, L.R.; Claiborne, C.F.; Rolfe, M.; Bolen, J.B.; Langston, S.P. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature, 2009, 458(7239), 732-736.
[http://dx.doi.org/10.1038/nature07884] [PMID: 19360080]
[24]
Gong, L.; Yeh, E.T. Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway. J. Biol. Chem., 1999, 274(17), 12036-12042.
[http://dx.doi.org/10.1074/jbc.274.17.12036] [PMID: 10207026]
[25]
Soucy, T.A.; Smith, P.G.; Rolfe, M. Targeting NEDD8-activated cullin-RING ligases for the treatment of cancer. Clin. Cancer Res., 2009, 15(12), 3912-3916.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0343] [PMID: 19509147]
[26]
Read, M.A.; Brownell, J.E.; Gladysheva, T.B.; Hottelet, M.; Parent, L.A.; Coggins, M.B.; Pierce, J.W.; Podust, V.N.; Luo, R.S.; Chau, V.; Palombella, V.J. Nedd8 modification of cul-1 activates SCF(β(TrCP))-dependent ubiquitination of IkappaBalpha. Mol. Cell. Biol., 2000, 20(7), 2326-2333.
[http://dx.doi.org/10.1128/MCB.20.7.2326-2333.2000] [PMID: 10713156]
[27]
Yada, M.; Hatakeyama, S.; Kamura, T.; Nishiyama, M.; Tsunematsu, R.; Imaki, H.; Ishida, N.; Okumura, F.; Nakayama, K.; Nakayama, K.I. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J., 2004, 23(10), 2116-2125.
[http://dx.doi.org/10.1038/sj.emboj.7600217] [PMID: 15103331]
[28]
Kobayashi, A.; Kang, M.I.; Okawa, H.; Ohtsuji, M.; Zenke, Y.; Chiba, T.; Igarashi, K.; Yamamoto, M. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol., 2004, 24(16), 7130-7139.
[http://dx.doi.org/10.1128/MCB.24.16.7130-7139.2004] [PMID: 15282312]
[29]
Lau, A.; Villeneuve, N.F.; Sun, Z.; Wong, P.K.; Zhang, D.D. Dual roles of Nrf2 in cancer. Pharmacol. Res., 2008, 58(5-6), 262-270.
[http://dx.doi.org/10.1016/j.phrs.2008.09.003] [PMID: 18838122]
[30]
Podust, V.N.; Brownell, J.E.; Gladysheva, T.B.; Luo, R.S.; Wang, C.; Coggins, M.B.; Pierce, J.W.; Lightcap, E.S.; Chau, V.A. Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination. Proc. Natl. Acad. Sci. USA, 2000, 97(9), 4579-4584.
[http://dx.doi.org/10.1073/pnas.090465597] [PMID: 10781063]
[31]
Wang, M.; Medeiros, B.C.; Erba, H.P.; DeAngelo, D.J.; Giles, F.J.; Swords, R.T. Targeting protein neddylation: a novel therapeutic strategy for the treatment of cancer. Expert Opin. Ther. Targets, 2011, 15(3), 253-264.
[http://dx.doi.org/10.1517/14728222.2011.550877] [PMID: 21219242]
[32]
Abida, W.M.; Nikolaev, A.; Zhao, W.; Zhang, W.; Gu, W. FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity. J. Biol. Chem., 2007, 282(3), 1797-1804.
[http://dx.doi.org/10.1074/jbc.M609001200] [PMID: 17098746]
[33]
Xirodimas, D.P.; Saville, M.K.; Bourdon, J.C.; Hay, R.T.; Lane, D.P. Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell, 2004, 118(1), 83-97.
[http://dx.doi.org/10.1016/j.cell.2004.06.016] [PMID: 15242646]
[34]
Kane, R.C.; Bross, P.F.; Farrell, A.T.; Pazdur, R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist, 2003, 8(6), 508-513.
[http://dx.doi.org/10.1634/theoncologist.8-6-508] [PMID: 14657528]
[35]
Kane, R.C.; Dagher, R.; Farrell, A.; Ko, C.W.; Sridhara, R.; Justice, R.; Pazdur, R. Bortezomib for the treatment of mantle cell lymphoma. Clin. Cancer Res., 2007, 13(18 Pt 1), 5291-5294.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0871] [PMID: 17875757]
[36]
Brownell, J.E.; Sintchak, M.D.; Gavin, J.M.; Liao, H.; Bruzzese, F.J.; Bump, N.J.; Soucy, T.A.; Milhollen, M.A.; Yang, X.; Burkhardt, A.L.; Ma, J.; Loke, H.K.; Lingaraj, T.; Wu, D.; Hamman, K.B.; Spelman, J.J.; Cullis, C.A.; Langston, S.P.; Vyskocil, S.; Sells, T.B.; Mallender, W.D.; Visiers, I.; Li, P.; Claiborne, C.F.; Rolfe, M.; Bolen, J.B.; Dick, L.R. Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Mol. Cell, 2010, 37(1), 102-111.
[http://dx.doi.org/10.1016/j.molcel.2009.12.024] [PMID: 20129059]
[37]
Toth, J.I.; Yang, L.; Dahl, R.; Petroski, M.D. A gatekeeper residue for NEDD8-activating enzyme inhibition by MLN4924. Cell Rep., 2012, 1(4), 309-316.
[http://dx.doi.org/10.1016/j.celrep.2012.02.006] [PMID: 22832224]
[38]
Milhollen, M.A.; Thomas, M.P.; Narayanan, U.; Traore, T.; Riceberg, J.; Amidon, B.S.; Bence, N.F.; Bolen, J.B.; Brownell, J.; Dick, L.R.; Loke, H.K.; McDonald, A.A.; Ma, J.; Manfredi, M.G.; Sells, T.B.; Sintchak, M.D.; Yang, X.; Xu, Q.; Koenig, E.M.; Gavin, J.M.; Smith, P.G. Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924. Cancer Cell, 2012, 21(3), 388-401.
[http://dx.doi.org/10.1016/j.ccr.2012.02.009] [PMID: 22439935]
[39]
Xu, G.W.; Toth, J.I.; da Silva, S.R.; Paiva, S.L.; Lukkarila, J.L.; Hurren, R.; Maclean, N.; Sukhai, M.A.; Bhattacharjee, R.N.; Goard, C.A.; Medeiros, B.; Gunning, P.T.; Dhe-Paganon, S.; Petroski, M.D.; Schimmer, A.D. Mutations in UBA3 confer resistance to the NEDD8-activating enzyme inhibitor MLN4924 in human leukemic cells. PLoS One, 2014, 9(4)e93530
[http://dx.doi.org/10.1371/journal.pone.0093530] [PMID: 24691136]
[40]
Lu, P.; Liu, X.; Yuan, X.; He, M.; Wang, Y.; Zhang, Q.; Ouyang, P.K. Discovery of a novel NEDD8 activating enzyme inhibitor with piperidin-4-amine scaffold by structure-based virtual screening. ACS Chem. Biol., 2016, 11(7), 1901-1907.
[http://dx.doi.org/10.1021/acschembio.6b00159] [PMID: 27135934]
[41]
Lu, P.; Guo, Y.; Zhu, L.; Xia, Y.; Zhong, Y.; Wang, Y. A novel NAE/UAE dual inhibitor LP0040 blocks neddylation and ubiquitination leading to growth inhibition and apoptosis of cancer cells. Eur. J. Med. Chem., 2018, 154, 294-304.
[http://dx.doi.org/10.1016/j.ejmech.2018.05.027] [PMID: 29843100]
[42]
Gao, Q.; Yu, G.Y.; Shi, J.Y.; Li, L.H.; Zhang, W.J.; Wang, Z.C.; Yang, L.X.; Duan, M.; Zhao, H.; Wang, X.Y.; Zhou, J.; Qiu, S.J.; Jeong, L.S.; Jia, L.J.; Fan, J. Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target. Oncotarget, 2014, 5(17), 7820-7832.
[http://dx.doi.org/10.18632/oncotarget.2309] [PMID: 25229838]
[43]
Li, L.; Wang, M.; Yu, G.; Chen, P.; Li, H.; Wei, D.; Zhu, J.; Xie, L.; Jia, H.; Shi, J.; Li, C.; Yao, W.; Wang, Y.; Gao, Q.; Jeong, L.S.; Lee, H.W.; Yu, J.; Hu, F.; Mei, J.; Wang, P.; Chu, Y.; Qi, H.; Yang, M.; Dong, Z.; Sun, Y.; Hoffman, R.M.; Jia, L. Overactivated neddylation pathway as a therapeutic target in lung cancer J. Natl. Cancer Insti., 2014, 106(6), dju083.
[44]
Lukkarila, J.L.; da Silva, S.R.; Ali, M.; Shahani, V.M.; Xu, G.W.; Berman, J.; Roughton, A.; Dhe-Paganon, S.; Schimmer, A.D.; Gunning, P.T. Identification of NAE inhibitors exhibiting potent activity in leukemia cells: exploring the structural determinants of NAE specificity. ACS Med. Chem. Lett., 2011, 2(8), 577-582.
[http://dx.doi.org/10.1021/ml2000615] [PMID: 24900352]
[45]
Nawrocki, S.T.; Kelly, K.R.; Smith, P.G.; Espitia, C.M.; Possemato, A.; Beausoleil, S.A.; Milhollen, M.; Blakemore, S.; Thomas, M.; Berger, A.; Carew, J.S. Disrupting protein NEDDylation with MLN4924 is a novel strategy to target cisplatin resistance in ovarian cancer. Clin. Cancer Res., 2013, 19(13), 3577-3590.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-3212] [PMID: 23633453]
[46]
Senise, L.V.; Yamashita, K.M.; Santoro, M.L. Bothrops jararaca envenomation: Pathogenesis of hemostatic disturbances and intravascular hemolysis. Exp. Biol. Med. (Maywood), 2015, 240(11), 1528-1536.
[http://dx.doi.org/10.1177/1535370215590818] [PMID: 26080462]
[47]
Chou, T.C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev., 2006, 58(3), 621-681.
[http://dx.doi.org/10.1124/pr.58.3.10] [PMID: 16968952]
[48]
Chou, T.C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res., 2010, 70(2), 440-446.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1947] [PMID: 20068163]
[49]
Yadav, S.; Joshi, S.; Qadar Pasha, M.A.; Pasha, S. Antimicrobial activity and mode of action of novel, N-terminal tagged tetra-peptidomimetics. MedChemComm, 2013, 4, 874-880.
[http://dx.doi.org/10.1039/c3md20311e]

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