Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

1'-methylspiro[indoline-3,4'-piperidine] Derivatives: Design, Synthesis, Molecular Docking and Anti-tumor Activity Studies

Author(s): Junjian Li, Lianbao Ye*, Yuanyuan Wang, Ying Liu, Xiaobao Jin and Ming Li

Volume 18, Issue 5, 2021

Published on: 17 November, 2020

Page: [490 - 498] Pages: 9

DOI: 10.2174/1570180817999201117150714

Price: $65

Abstract

Background: Spirocyclic indoline compounds widely exist in numerous natural products and synthetic molecules with significant biological activities. In recent years, these kinds of compounds have attracted extensive attention as potent anti-tumor agents in the fields of pharmacology and chemistry.

Objective: In this study, we focused on designing and synthesizing novel 1'-methylspiro[indoline- 3,4'-piperidine] derivatives, which were evaluated by preliminary bioactivity experiment in vitro and molecular docking.

Materials and Methods: The key intermediate 1'-methylspiro[indoline-3,4'-piperidine] (B4) reacted with benzenesulfonyl chloride with different substituents under alkaline condition to obtain its derivatives (B5-B10). We evaluated their antiproliferative activities against A549, BEL-7402 and HeLa cell lines by MTT assay. We performed the CDOCKER module in Accelrys Discovery Studio 2.5.5 for molecular docking of compound B5, and investigated the binding modes of compound B5 with three different target proteins.

Results: The results indicated that compounds B4-B10 exhibited good antiproliferative activities against the above three types of cell lines, in which compound B5 with chloride atom as electronwithdrawing substituent on a phenyl ring showed the highest potency against BEL-7402 cell lines (IC50=30.03±0.43 μg/mL). The results of molecular docking showed that the binding energies of the prominent bioactive compound B5 with CDK, c-Met, and EGFR protein crystals are -44.3583 kcal/mol, -38.3292 kcal/mol, -33.3653 kcal/mol, respectively.

Conclusion: 1'-methylspiro[indoline-3,4'-piperidine] and its six derivatives were synthesized and evaluated against BEL-7402, A 549, and Hela cell lines. Compound B5 showed significant inhibition on BEL-7402 cell lines. Molecular docking assays revealed that B5 as a ligand showed strong affinity and appropriate binding pose on the amino acid residues in active sites of the tested targets, which encourage us to conduct further evaluation such as the kinase experiment.

Keywords: Spirocyclic indoline derivatives, sulfonylation, anti-tumor, cytotoxicity, CDK, molecular docking.

Graphical Abstract

[1]
Atlihan-Gundogdu, E.; Ilem-Ozdemir, D.; Ekinci, M.; Ozgenc, E.; Demir, E.S.; Sánchez-Dengra, B.; González-Alvárez, I. Recent developments in cancer therapy and diagnosis. J. Pharm. Investig., 2020.
[http://dx.doi.org/10.1007/s40005-020-00473-0]
[2]
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.
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[3]
Ravalli Remella, S.B. Recent developments in cancer. J. Dev. Drugs, 2015, 04(02)
[http://dx.doi.org/10.4172/2329-6631.1000r001]]
[4]
Mao, Y.; Gao, L. Global Anti-cancer Drug R&D Report. Science & Technology Review, 2016, 34(11), 21-24.
[5]
Narwal, M.; Haikarainen, T.; Fallarero, A.; Vuorela, P.M.; Lehtiö, L. Screening and structural analysis of flavones inhibiting tankyrases. J. Med. Chem., 2013, 56(9), 3507-3517.
[http://dx.doi.org/10.1021/jm3018783] [PMID: 23574272]
[6]
Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; Huang, D.C.; Hymowitz, S.G.; Jin, S.; Khaw, S.L.; Kovar, P.J.; Lam, L.T.; Lee, J.; Maecker, H.L.; Marsh, K.C.; Mason, K.D.; Mitten, M.J.; Nimmer, P.M.; Oleksijew, A.; Park, C.H.; Park, C.M.; Phillips, D.C.; Roberts, A.W.; Sampath, D.; Seymour, J.F.; Smith, M.L.; Sullivan, G.M.; Tahir, S.K.; Tse, C.; Wendt, M.D.; Xiao, Y.; Xue, J.C.; Zhang, H.; Humerickhouse, R.A.; Rosenberg, S.H.; Elmore, S.W. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med., 2013, 19(2), 202-208.
[http://dx.doi.org/10.1038/nm.3048] [PMID: 23291630]
[7]
Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer, 2013, 13(10), 714-726.
[http://dx.doi.org/10.1038/nrc3599] [PMID: 24060863]
[8]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[9]
Santos, F.P.; Verstovsek, S. JAK2 inhibitors: What’s the true therapeutic potential? Blood Rev., 2011, 25(2), 53-63.
[http://dx.doi.org/10.1016/j.blre.2010.10.004] [PMID: 21095048]
[10]
Clark, M. P.; Laufersweiler, M. J.; Djung, F. J.; Natchus, M. G.; De, B. 6,7-Dihydro-5H-pyrazolo[1,2-a] pyrazol-1-ones which control inflammatory cytokines WO2003024973 2003.
[11]
Bell, I. M.; Gallicchio, S. N.; Theberge, C. R.; Zhang, X. F.; Stump, C.; Zartman, B. C. >Bicyclic anilide spirohydantoin cgrp receptor antagonists. US6486199 2002.
[12]
Embrey, M. W.; Perlow, D. S.; Wai, J. S.; Hoffman, J. M. Inhibitors of prenyl-protein transferase US6172076 2001.
[13]
Hamblett, C.; Kattar, S.; Mampreian, D.; Methot, J.; Miller, T.; Tempest, P. Aryl-Fused Spirocyclic Compounds U.S. W02007136605 2009.
[14]
Lippa, B.; Pan, G.; Corbett, M.; Li, C.; Kauffman, G.S.; Pandit, J.; Robinson, S.; Wei, L.; Kozina, E.; Marr, E.S.; Borzillo, G.; Knauth, E.; Barbacci-Tobin, E.G.; Vincent, P.; Troutman, M.; Baker, D.; Rajamohan, F.; Kakar, S.; Clark, T.; Morris, J. Synthesis and structure based optimization of novel Akt inhibitors. Bioorg. Med. Chem. Lett., 2008, 18(11), 3359-3363.
[http://dx.doi.org/10.1016/j.bmcl.2008.04.034] [PMID: 18456494]
[15]
Bissantz, C.; Grundschober, C.; Ratni, H. Indol-3-carbonyl-spiropiperidine derivatives as vlareceptor antagonists. W02007006688 2007.
[16]
Cassayre, J.; Molleyres, L. P.; Maienfisch, P.; Cederbaum, F. Spiropiperidine derivatives for controlling pests. WO2005061500 2011.
[17]
Bertamino, A.; Soprano, M.; Musella, S.; Rusciano, M.R.; Sala, M.; Vernieri, E.; Di Sarno, V.; Limatola, A.; Carotenuto, A.; Cosconati, S.; Grieco, P.; Novellino, E.; Illario, M.; Campiglia, P.; Gomez-Monterrey, I. Synthesis, in vitro, and in cell studies of a new series of [indoline-3,2¢-thiazolidine]-based p53 modulators. J. Med. Chem., 2013, 56(13), 5407-5421.
[http://dx.doi.org/10.1021/jm400311n] [PMID: 23802716]
[18]
You, W.K.; Sennino, B.; Williamson, C.W.; Falcón, B.; Hashizume, H.; Yao, L.C.; Aftab, D.T.; McDonald, D.M. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res., 2011, 71(14), 4758-4768.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2527] [PMID: 21613405]
[19]
Ye, L.; Tian, Y.; Li, Z.; Jin, H.; Zhu, Z.; Wan, S.; Zhang, J.; Yu, P.; Zhang, J.; Wu, S. Design, synthesis and molecular docking studies of some novel spiro[indoline-3, 4¢-piperidine]-2-ones as potential c-Met inhibitors. Eur. J. Med. Chem., 2012, 50, 370-375.
[http://dx.doi.org/10.1016/j.ejmech.2012.02.016] [PMID: 22381355]
[20]
Li, J.; Wu, N.; Tian, Y.; Zhang, J.; Wu, S. Aminopyridyl/Pyrazinyl Spiro[indoline-3,4¢-piperidine]-2-ones As Highly Selective and Efficacious c-Met/ALK Inhibitors. ACS Med. Chem. Lett., 2013, 4(8), 806-810.
[http://dx.doi.org/10.1021/ml400203d] [PMID: 24900750]
[21]
Ye, L.; Zhao, T.; Du, W.; Li, A.; Gao, W.; Li, J.; Wang, L.; Chen, W. Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 1233-1246.
[http://dx.doi.org/10.1080/14756366.2019.1634704] [PMID: 31286784]
[22]
Wu, S.G.; Zhang, J.J.; Wu, S.Y.; Xu, W.; Wang, H.T.; Liu, Z.Q.; Wan, S.H. CN101857594 2010.
[23]
Ghorab, M.M.; Ragab, F.A.; Heiba, H.I.; El-Gazzar, M.G.; Zahran, S.S. Synthesis, anticancer and radiosensitizing evaluation of some novel sulfonamide derivatives. Eur. J. Med. Chem., 2015, 92, 682-692.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.036] [PMID: 25618015]
[24]
Guo, Z.; Xu, Y.; Peng, Y.; Quan, W.; Xie, P.; Wu, L.; Jiang, J.; Wang, L.; Liu, X.; Liu, X. Haroon Ur Rashid. Design, synthesis and evaluation of novel (S)-tryptamine derivatives containing an allyl group and an aryl sulfonamide unit as anticancer agents. Bioorg. Med. Chem. Lett., 2019, 29(9), 1133-1137.
[http://dx.doi.org/10.1016/j.bmcl.2019.02.023] [PMID: 30842032]
[25]
Feng, Y.; Teng, X.; Gu, J.; Yu, B.; Luo, Y.; Ye, L.J.M.C.R. Novel anti-cancer agents: design, synthesis, biological activity, molecular docking, and MD simulations of 2, 3, 4, 5-tetrahydro-1H-pyrido-[4,3-b] indole derivatives. Med. Chem. Res., 2018.
[26]
Ye, L.; Wu, J.; Chen, W.; Feng, Y.; Shen, Z.J.R.A. Novel anti-cancer agents based on germacrone: design, synthesis, biological activity, docking studies and MD simulations. RSC Advances, 2017, 7(7), 3760-3767.
[http://dx.doi.org/10.1039/C6RA26944C]
[27]
Ye, L.; Wu, J.; Yang, J.; Chen, W.; Luo, Y.; Zhang, Y. Design, synthesis and molecular docking analysis of some novel 7-[(quinolin-6-yl) methyl] purines as potential c-Met inhibitors. Med. Chem. Res., 2015, 24, 3327-3333.
[http://dx.doi.org/10.1007/s00044-015-1383-z]
[28]
Jing, E.; Ye, L.; Shan, G.; Zhi, L.; Fei, H.; Wei, H.; Song, W.; Hao, Z. How different substitution positions of f, cl atoms in benzene ring of 5-methylpyrimidine pyridine derivatives affect the inhibition ability of egfr(l858r/t790m/c797s) inhibitors: A molecular dynamics simulation study. Molecules, 2020, 25(4), 895.
[http://dx.doi.org/10.3390/molecules25040895]
[29]
Comoglio, P.M.; Giordano, S.; Trusolino, L. Drug development of MET inhibitors: Targeting oncogene addiction and expedience. Nat. Rev. Drug Discov., 2008, 7(6), 504-516.
[http://dx.doi.org/10.1038/nrd2530] [PMID: 18511928]
[30]
Romu, A.A.; Lei, Z.; Zhou, B.; Chen, Z.S.; Korlipara, V. Design, synthesis and biological evaluation of WZ4002 analogues as EGFR inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(21), 4832-4837.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.048] [PMID: 28974338]
[31]
Benkheil, M.; Paeshuyse, J.; Neyts, J.; Van Haele, M.; Roskams, T.; Liekens, S. HCV-induced EGFR-ERK signaling promotes a pro-inflammatory and pro-angiogenic signature contributing to liver cancer pathogenesis. Biochem. Pharmacol., 2018, 155, 305-315.
[http://dx.doi.org/10.1016/j.bcp.2018.07.011] [PMID: 30012461]
[32]
Tadesse, S.; Anshabo, A.T.; Portman, N.; Lim, E.; Tilley, W.; Caldon, C.E.; Wang, S. Targeting CDK2 in cancer: Challenges and opportunities for therapy. Drug Discov. Today, 2020, 25(2), 406-413.
[http://dx.doi.org/10.1016/j.drudis.2019.12.001] [PMID: 31839441]
[33]
Abdel Latif, N.A.; Batran, R.Z.; Khedr, M.A.; Abdalla, M.M. 3- Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis, molecular modeling and QSAR studies. Bioorg. Chem., 2016, 67, 116-129.
[http://dx.doi.org/10.1016/j.bioorg.2016.06.005] [PMID: 27372186 ]
[34]
Sanchez-Martinez, C.; Gelbert, L.M.; Lallena, M.J.; De Dios, A.J.C. ChemInform abstract: Cyclin dependent kinase (cdk) inhibitors as anticancer drugs. ChemInform, 2015, 46(40)

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