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Current Pharmaceutical Design

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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Design, Synthesis and Antitumor Activity of Novel Dispiro[oxindole-cyclohexanone]- pyrrolidines

Author(s): Magy Gouda, Majed Bawazeer, Lamees Hegazy, Mohamed Azab, Mohamed Elagawany, Mostafa Rateb, Mohammed Yaseen and Bahaa Elgendy*

Volume 28, Issue 3, 2022

Published on: 25 June, 2021

Page: [198 - 207] Pages: 10

DOI: 10.2174/1381612827666210625160627

Abstract

Background: Spirooxindoles are privileged scaffolds in medicinal chemistry, which were identified through Wang’s pioneering work as inhibitors of MDM2-p53 interactions.

Objective: To design and synthesize 2,6-diarylidenecyclohexanones and dispiro[oxindole-cyclohexanone]- pyrrolidines having potential antitumor effect.

Methods: Dispiro[oxindole-cyclohexanone]-pyrrolidines 6a-h were synthesized in a regioselective manner via 1,3-dipolar cycloaddition reaction of 2,6-diarylidenecyclohexanones 3a-h, isatin, and sarcocine. Compounds 6a-h were alkylated to give (7-10)a,b. All compounds were evaluated in vitro for their antitumor activity and cytotoxic selectivity against breast cancer cell lines (MCF-7 and MDA-MB-231), breast fibrosis cell line (MCF10a), and placental cancer cell line (JEG-3). Molecular modeling inside the MDM2 binding site was performed using AutoDock4.2.

Results: Synthesized compounds showed antitumor activity comparable to tamoxifen and compounds 3a,b,f,g and 9a,b showed selective cytotoxicity against tumor cells but reduced toxicity toward MCF-10a cells. Molecular modelling shows that both classes of synthesized compounds are predicted to fit the deep hydrophobic cleft on the surface of MDM2 and mimic the interactions between p53 and MDM2.

Conclusion: The synthesized compounds have antitumor activity against MCF-7, MDA-MB-231, and JEG-3. Few compounds showed a selective cytotoxic effect and may have the potential to inhibit MDM2 and stimulate p53. In the future, studies regarding the optimization of medicinal chemistry as well as mechanistic studies will be conducted to enhance the inhibition effect of identified compounds and elucidate their mechanism of action.

Keywords: Spiro-oxindoles, diarylidenecyclohexanones, 1, 3-dipolar cycloaddition reactions, antitumor, molecular modeling, MDM2, p53.

« Previous Next »
[1]
Lalit K, Shashi B, Kamal J. The diverse pharmacological importance of indole derivatives: A review. Int J Res Pharm Sci 2012; 2(2): 23-33.
[2]
Molteni G, Silvani A. Spiro-2-oxindoles via 1,3-dipolar cycloadditions. A decade update. European J Organic Chem 2021; 2021: 1653-75.
[http://dx.doi.org/10.1002/ejoc.202100121]
[3]
Zhou LM, Qu RY, Yang GF. An overview of spirooxindole as a promising scaffold for novel drug discovery. Expert Opin Drug Discov 2020; 15(5): 603-25.
[http://dx.doi.org/10.1080/17460441.2020.1733526] [PMID: 32106717]
[4]
Satheeshkumar D, Kottai Muthu A, Manavalan R. In-vivo antioxidant and lipid peroxidation effect of whole plant of Ionidium suffruticosum (Ging.) in rats fed with high fat diet. Asian J Pharm Clin Res 2012; 5: 132-5.
[5]
Kaushik NK, Kaushik N, Attri P, et al. Biomedical importance of indoles. Molecules 2013; 18(6): 6620-62.
[http://dx.doi.org/10.3390/molecules18066620] [PMID: 23743888]
[6]
Bartoli RD. Curr Org Chem 2005; 9: 163-78.
[http://dx.doi.org/10.2174/1385272053369204]
[7]
Badillo JJ, Hanhan NV, Franz AK. Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery. Curr Opin Drug Discov Devel 2010; 13(6): 758-76.
[PMID: 21061236]
[8]
Yu B, Yu D-Q, Liu H-M. Spirooxindoles: Promising scaffolds for anticancer agents. Eur J Med Chem 2015; 97: 673-98.
[http://dx.doi.org/10.1016/j.ejmech.2014.06.056] [PMID: 24994707]
[9]
Wang K, Zhou XY, Wang YY, et al. Macrophyllionium and macrophyllines A and B, oxindole alkaloids from Uncaria macrophylla. J Nat Prod 2011; 74(1): 12-5.
[http://dx.doi.org/10.1021/np1004938] [PMID: 21070010]
[10]
Jossang A, Jossang P, Hadi HA, Sevenet T, Bodo B. Horsfiline, an oxindole alkaloid from Horsfieldia superba. J Org Chem 1991; 56(23): 6527-30.
[http://dx.doi.org/10.1021/jo00023a016]
[11]
Jones K, Wilkinson J. A total synthesis of horsfiline via aryl radical cyclisation. J Chem Soc Chem Commun 1992; (24): 1767-9.
[http://dx.doi.org/10.1039/c39920001767]
[12]
Cui C-B, Kakeya H, Osada H. Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron 1996; 52(39): 12651-66.
[http://dx.doi.org/10.1016/0040-4020(96)00737-5]
[13]
Sebahar PR, Williams RM. The asymmetric total synthesis of (+)- and (−)-spirotryprostatin B. J Am Chem Soc 2000; 122(23): 5666-7.
[http://dx.doi.org/10.1021/ja001133n]
[14]
Abadi AH, Abou-Seri SM, Abdel-Rahman DE, Klein C, Lozach O, Meijer L. Synthesis of 3-substituted-2-oxoindole analogues and their evaluation as kinase inhibitors, anticancer and antiangiogenic agents. Eur J Med Chem 2006; 41(3): 296-305.
[http://dx.doi.org/10.1016/j.ejmech.2005.12.004] [PMID: 16494969]
[15]
Ding K, Lu Y, Nikolovska-Coleska Z, et al. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 2006; 49(12): 3432-5.
[http://dx.doi.org/10.1021/jm051122a] [PMID: 16759082]
[16]
Yu S, Qin D, Shangary S, et al. Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 2009; 52(24): 7970-3.
[http://dx.doi.org/10.1021/jm901400z] [PMID: 19928922]
[17]
Sun SH, Zheng M, Ding K, Wang S, Sun Y. A small molecule that disrupts Mdm2-p53 binding activates p53, induces apoptosis and sensitizes lung cancer cells to chemotherapy. Cancer Biol Ther 2008; 7(6): 845-52.
[http://dx.doi.org/10.4161/cbt.7.6.5841] [PMID: 18340116]
[18]
Xie X, Xiong S-S, Li X, Huang H, Wu F-B, Shen P-F, et al. Design and organocatalytic synthesis of spirooxindole–cyclopentene–isoxazole hybrids as novel MDM2–p53 inhibitors. Org Chem Front 2021; 8(8): 1836-43.
[http://dx.doi.org/10.1039/D0QO01626H]
[19]
Liu S-J, Zhao Q, Peng C, et al. Design, synthesis, and biological evaluation of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives as novel glutathione peroxidase 4/mouse double minute 2 dual inhibitors that inhibit breast adenocarcinoma cell proliferation. Eur J Med Chem 2021; 217: 113359.
[http://dx.doi.org/10.1016/j.ejmech.2021.113359] [PMID: 33725632]
[20]
Zhao Y, Yu S, Sun W, et al. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J Med Chem 2013; 56(13): 5553-61.
[http://dx.doi.org/10.1021/jm4005708] [PMID: 23786219]
[21]
Mohammad RM, Wu J, Azmi AS, et al. An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals. Mol Cancer 2009; 8: 115.
[http://dx.doi.org/10.1186/1476-4598-8-115] [PMID: 19958544]
[22]
Belal A. El-Gendy Bel-D. Pyrrolizines: Promising scaffolds for anticancer drugs. Bioorg Med Chem 2014; 22(1): 46-53.
[http://dx.doi.org/10.1016/j.bmc.2013.11.040] [PMID: 24331756]
[23]
Flaveny CA, Griffett K, El-Gendy Bel-D, et al. Broad anti-tumor activity of a small molecule that selectively targets the warburg effect and lipogenesis. Cancer Cell 2015; 28(1): 42-56.
[http://dx.doi.org/10.1016/j.ccell.2015.05.007] [PMID: 26120082]
[24]
Eno MR. El-Gendy Bel-D, Cameron MD. P450 3A-catalyzed O-dealkylation of lapatinib induces mitochondrial stress and activates Nrf2. Chem Res Toxicol 2016; 29(5): 784-96.
[http://dx.doi.org/10.1021/acs.chemrestox.5b00524] [PMID: 26958860]
[25]
Ibrahim TS, Hawwas MM, Taher ES, et al. Design and synthesis of novel pyrazolo[3,4-d]pyrimidin-4-one bearing quinoline scaffold as potent dual PDE5 inhibitors and apoptotic inducers for cancer therapy. Bioorg Chem 2020; 105: 104352.
[http://dx.doi.org/10.1016/j.bioorg.2020.104352] [PMID: 33080494]
[26]
Elzahhar PA, Abd El Wahab SM, Elagawany M, et al. Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases. Eur J Med Chem 2020; 200: 112439.
[http://dx.doi.org/10.1016/j.ejmech.2020.112439] [PMID: 32485532]
[27]
Kalirajan R, Sivakumar SU, Jubie S, Gowramma B, Suresh B. Synthesis and biological evaluation of some heterocyclic derivatives of Chalcones. Int J Chemtech Res 2009; 1(1): 27-34.
[28]
Rahman AFMM, Ali R, Jahng Y, Kadi AA. A facile solvent free Claisen-Schmidt reaction: synthesis of α,α′-bis-(substituted-benzylidene)cycloalkanones and α,α′-bis-(substituted-alkylidene) cycloalkanones. Molecules 2012; 17(1): 571-83.
[http://dx.doi.org/10.3390/molecules17010571] [PMID: 22231494]
[29]
Mohammadi ZG, Badiei A, Abbasi A, et al. Cross-aldol Condensation of Cycloalkanones and Aromatic Aldehydes in the Presence of Nanoporous Silica-based Sulfonic Acid (SiO2-Pr-SO3H) under Solvent Free Conditions. Chin J Chem 2009; 27(8): 1537-42.
[http://dx.doi.org/10.1002/cjoc.200990259]
[30]
Shalaby EM, Girgis AS, Moustafa AM, ElShaabiny AM, El-Gendy BM, Mabied AF. Regioselective synthesis, stereochemical structure, spectroscopic characterization and geometry optimization of dispiro. [3H-indole-3,2′-pyrrolidine-3′,3″-piperidines] J Mol Struct 2014; 1075: 327-34.
[http://dx.doi.org/10.1016/j.molstruc.2014.07.014]
[31]
Mabied AF, Girgis AS, Shalaby ESM, George RF, El-Gendy BM, Baselious FN. Stereoselective Synthesis, Structural and Spectroscopic Study of 4,5,11-Triazatricyclo[6.2.1.0*2,6*]Undec-5-ene. J Heterocycl Chem 2016; 53(4): 1074-80.
[http://dx.doi.org/10.1002/jhet.2440]
[32]
Amal Raj A, Raghunathan R. A novel entry into a new class of spiroheterocyclic framework: Regioselective synthesis of dispiro [oxindole-cyclohexanone]-pyrrolidines and dispiro[oxindole-hexa-hydroindazole]pyrrolidines. Tetrahedron 2001; 57(52): 10293-8.
[http://dx.doi.org/10.1016/S0040-4020(01)01042-0]
[33]
Wang XJ, Sidhu K, Zhang L, et al. Bromo-directed N-2 alkylation of NH-1,2,3-triazoles: efficient synthesis of poly-substituted 1,2,3-triazoles. Org Lett 2009; 11(23): 5490-3.
[http://dx.doi.org/10.1021/ol902334x] [PMID: 19905002]
[34]
Kurkin AV, Bernovskaya AA, Yurovskaya MA. Synthesis of N-alkylanthranilamides with a chiral substituent at the nitrogen atom. Tetrahedron Asymmetry 2010; 21(17): 2100-7.
[http://dx.doi.org/10.1016/j.tetasy.2010.07.001]
[35]
Mete E, Gul HI, Kazaz C. Synthesis of 1-Aryl-3-phenethylamino-1-propanone hydrochlorides as possible potent cytotoxic agents. Molecules 2007; 12(12): 2579-88.
[http://dx.doi.org/10.3390/12122579] [PMID: 18259144]
[36]
Sridhar SK, Ramesh A. Synthesis and pharmacological activities of hydrazones, Schiff and Mannich bases of isatin derivatives. Biol Pharm Bull 2001; 24(10): 1149-52.
[http://dx.doi.org/10.1248/bpb.24.1149] [PMID: 11642321]
[37]
Gollner A, Rudolph D, Arnhof H, et al. Discovery of novel spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds as chemically stable and orally active inhibitors of the MDM2-p53 interaction. J Med Chem 2016; 59(22): 10147-62.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00900] [PMID: 27775892]
[38]
Pettersen EF, Goddard TD, Huang CC, et al. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004; 25(13): 1605-12.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[39]
Cousins KR. ChemDraw Ultra 9.0. CambridgeSoft, 100 CambridgePark Drive, Cambridge, MA 02140. J Am Chem Soc 2005; 127(11): 4115-6. Available from: www. cambridgesoft.com
[40]
Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30(16): 2785-91.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[41]
Biçer A, Taslimi P, Yakalı G, Gülçin I, Serdar Gültekin M, Turgut Cin G. Synthesis, characterization, crystal structure of novel bis-thiomethylcyclohexanone derivatives and their inhibitory properties against some metabolic enzymes. Bioorg Chem 2019; 82: 393-404.
[http://dx.doi.org/10.1016/j.bioorg.2018.11.001] [PMID: 30428418]
[42]
Brown CJ, Cheok CF, Verma CS, Lane DP. Reactivation of p53: from peptides to small molecules. Trends Pharmacol Sci 2011; 32(1): 53-62.
[http://dx.doi.org/10.1016/j.tips.2010.11.004] [PMID: 21145600]
[43]
Madan E, Parker TM, Bauer MR, et al. The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53. J Biol Chem 2018; 293(12): 4262-76.
[http://dx.doi.org/10.1074/jbc.RA117.000950] [PMID: 29382728]
[44]
Bazzaro M, Linder S. Dienone compounds: Targets and pharmacological responses. J Med Chem 2020; 63(24): 15075-93.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00812] [PMID: 33146523]
[45]
Ding K, Lu Y, Nikolovska-Coleska Z, et al. Structure-based design of potent non-peptide MDM2 inhibitors. J Am Chem Soc 2005; 127(29): 10130-1.
[http://dx.doi.org/10.1021/ja051147z] [PMID: 16028899]

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