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2000
Volume 21, Issue 18
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

Ionic immobilized liquids and multi-component reactions are integral to green chemistry, facilitating the synthesis of biologically active compounds, such as xanthene and acridine derivatives. These approaches have garnered significant attention in recent years.

Objective

The aim of this study was to synthesize novel xanthene and acridine derivatives with diverse substituents and heterocyclic rings. Furthermore, the research sought to evaluate their anticancer activity against various cancer cell lines and analyze their structure-activity relationships (SAR) to determine how structural modifications impact their biological effectiveness.

Methods

The core compounds in this study were synthesized from cyclohexane-1,3-dione and triethoxymethane under two distinct reaction conditions. The first involved the use of a solvent with either EtN or NHOAc as a catalyst, while the second employed a solvent-free approach using an ionic liquid catalyst (ILs).

Results

The anti-proliferative activity of all synthesized compounds was evaluated against six selected cancer cell lines, revealing that many compounds exhibited significant inhibitory effects. Furthermore, their inhibitory potential against tyrosine kinases and Pim-1 kinases was assessed, along with an investigation of their mechanism of action on tyrosine kinases.

Conclusion

The anti-proliferative activity of the newly synthesized compounds was evaluated against six cancer cell lines. Many of the compounds exhibited strong inhibitory effects not only against the tested cancer cell lines but also against tyrosine kinases and Pim-1 kinases.

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References

  1. Arbabi JamS. SarrafiY. MalekiB. Immobilization of ionic liquid–triethanolammonium bicarbonate on magnetic nanoparticles as an efficient catalyst for knovenegel condensation.Polycycl. Aromat. Compd.20244474364437510.1080/10406638.2023.2247129
    [Google Scholar]
  2. Abu ZarinM.A. ZainolM.M. RamliN.A.S. AminN.A.S. Zeolite immobilized ionic liquid as an effective catalyst for conversion of biomass derivatives to levulinic acid.Molecular Catalysis202252811250610.1016/j.mcat.2022.112506
    [Google Scholar]
  3. JahanbakhshiA. FarahiM. Immobilized sulfonic acid functionalized ionic liquid on magnetic cellulose as a novel catalyst for the synthesis of triazolo[4,3-a]pyrimidines.Arab. J. Chem.2022151210431110.1016/j.arabjc.2022.104311
    [Google Scholar]
  4. PatersonR. AlharbiA.A. WillsC. DixonC. ŠillerL. ChamberlainT.W. GriffithsA. CollinsS.M. WuK. SimmonsM.D. BourneR.A. LovelockK.R.J. SeymourJ. KnightJ.G. DohertyS. Heteroatom modified polymer immobilized ionic liquid stabilized ruthenium nanoparticles: Efficient catalysts for the hydrolytic evolution of hydrogen from sodium borohydride.Molecul. Catal.202252811247610.1016/j.mcat.2022.112476
    [Google Scholar]
  5. WangL. LuJ. WangY. WangH. WangJ. RenT. Preparation and characterization of novel cyclohexene-to-adipic acid catalyst with ionic liquid phosphotungstate immobilized on MIL-101 nanocages based on Cr-N coordination.J. Mol. Struct.2023127113397310.1016/j.molstruc.2022.133973
    [Google Scholar]
  6. ElyasiZ. GhomiJ.S. NajafiG.R. Ultrasound-Engineered fabrication of immobilized molybdenum complex on Cross-Linked poly (Ionic Liquid) as a new acidic catalyst for the regioselective synthesis of pharmaceutical polysubstituted spiro compounds.Ultrason. Sonochem.20217510561410.1016/j.ultsonch.2021.10561434111724
    [Google Scholar]
  7. WireduB. AmarasekaraA.S. Synthesis of a silica-immobilized Brönsted acidic ionic liquid catalyst and hydrolysis of cellulose in water under mild conditions.Catal. Commun.201448414410.1016/j.catcom.2014.01.021
    [Google Scholar]
  8. SunJ. YangJ. LiS. XuX. Basic ionic liquid immobilized oxides as heterogeneous catalyst for biodiesel synthesis from waste cooking oil.Catal. Commun.201683353810.1016/j.catcom.2016.05.002
    [Google Scholar]
  9. LiJ. NiH. ZhangW. LaiZ. JinH. ZengL. CuiS. A multicomponent reaction for modular assembly of indole-fused heterocycles.Chem. Sci. (Camb.)202415145211521710.1039/D4SC00522H38577354
    [Google Scholar]
  10. ZelekeD. DamenaT. Advance in green synthesis of pharmacological important heterocycles using multicomponent reactions and magnetic nanocatalysts (MNCs).Resul. Chem.2024710128310.1016/j.rechem.2023.101283
    [Google Scholar]
  11. LiJ. GuA. NongX.M. ZhaiS. YueZ.Y. LiM.Y. LiuY. Six‐membered aromatic nitrogen heterocyclic anti‐tumor agents: Synthesis and applications.Chem. Rec.20232312e20230029310.1002/tcr.20230029338010365
    [Google Scholar]
  12. GoodellJ.R. MadhokA.A. HiasaH. FergusonD.M. Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity.Bioorg. Med. Chem.200614165467548010.1016/j.bmc.2006.04.04416713270
    [Google Scholar]
  13. ChibaleK. VisserM. van SchalkwykD. SmithP.J. SaravanamuthuA. FairlambA.H. Exploring the potential of xanthene derivatives as trypanothione reductase inhibitors and chloroquine potentiating agents.Tetrahedron200359132289229610.1016/S0040‑4020(03)00240‑0
    [Google Scholar]
  14. KumarA. ParveenM. ShahabA.A. NamiS.A. AzamM. AnsariM.S. FarooqI. AlamM. Efficacy of the ionic liquid 1,4-bis(carboxymethyl)piperazine-1,4-diium chloride as a catalyst for xanthenes/acridines synthesis: Spectral characterization, x-ray structure, and nematicidal activity.J. Saudi Chem. Soc.20242810180710.1016/j.jscs.2024.101807
    [Google Scholar]
  15. BanerjeeA.G. KothapalliL.P. SharmaP.A. ThomasA.B. NandaR.K. ShrivastavaS.K. KhatanglekarV.V. A facile microwave assisted one pot synthesis of novel xanthene derivatives as potential anti-inflammatory and analgesic agents.Arab. J. Chem.20169S480S48910.1016/j.arabjc.2011.06.001
    [Google Scholar]
  16. HafezH.N. HegabM.I. Ahmed-FaragI.S. A facile regioselective synthesis of novel spiro-thioxanthene and spiro-xanthene-9′,2-[1,3,4]thiadiazole derivatives as potential analgesic and anti-inflammatory agents.Bioorg. Med. Chem. Lett.2008184538454310.1016/j.bmcl.2008.07.042
    [Google Scholar]
  17. RenY. RuanY. ChengB. LiL. LiuJ. FangY. ChenJ. Design, synthesis and biological evaluation of novel acridine and quinoline derivatives as tubulin polymerization inhibitors with anticancer activities.Bioorg. Med. Chem.20214611637610.1016/j.bmc.2021.11637634455231
    [Google Scholar]
  18. DuttaA.K. GogoiP. SaikiaS. BorahR.N. N-disulfo-1,1,3,3-tetramethylguanidinium carboxylate ionic liquids as reusable homogeneous catalysts for multicomponent synthesis of tetrahydrobenzo[ a]xanthene and tetrahydrobenzo[ a]acridine derivatives.J. Mol. Liq.201722558559110.1016/j.molliq.2016.11.112
    [Google Scholar]
  19. WanY. ZhangX.X. WangC. ZhaoL.L.L. ChenL.F. LiuG.X. HuangS. YueS. ZhangW.L. WuH. The first example of glucose-containingBrønsted acid synthesis and catalysis: Efficient synthesis of tetrahydrobenzo[α]xanthens and tetrahydrobenzo[α]acridines in water.Tetrahedron2013693947395010.1016/j.tet.2013.03.029
    [Google Scholar]
  20. Le BrisM-T. MugnierJ. BoursonJ. ValeurB. Spectral properties of a new flourescent dye emitting in the red: A benzoxazinone derivative.Chem. Phys. Lett.19841061-212412710.1016/0009‑2614(84)87024‑4
    [Google Scholar]
  21. YinW. ZhuH. WangR. A sensitive and selective fluorescence probe based fluorescein for detection of hypochlorous acid and its application for biological imaging.Dyes Pigments201410712713210.1016/j.dyepig.2014.03.012
    [Google Scholar]
  22. ArnoczkyS.P. LavagninoM. WhallonJ.H. HoonjanA. In situ cell nucleus deformation in tendons under tensile load; a morphological analysis using confocal laser microscopy.J. Orthop. Res.2002201293510.1016/S0736‑0266(01)00080‑811853087
    [Google Scholar]
  23. LiM.Y. ZhaiS. NongX.M. GuA. LiJ. LinG.Q. LiuY. Trisubstituted alkenes featuring aryl groups: stereoselective synthetic strategies and applications.Sci. China Chem.20236651261128710.1007/s11426‑022‑1515‑5
    [Google Scholar]
  24. CuiZ. LiX. LiL. ZhangB. GaoC. ChenY. TanC. LiuH. XieW. YangT. JiangY. Design, synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment.Bioorg. Med. Chem.201624226126910.1016/j.bmc.2015.12.01126707846
    [Google Scholar]
  25. WilliamsD. KocerhaJ. AikenK. SeymourA.M. BlountG. DouglasD. Abstract 1923 anti-cancer activity of acridine derivatives in lung and prostate cancer cells.J. Biol. Chem.2024300310610910.1016/j.jbc.2024.106109
    [Google Scholar]
  26. de M Silva, M.; Macedo, T.S.; Teixeira, H.M.P.; Moreira, D.R.M.; Soares, M.B.P.; da C Pereira, A.L.; de L Serafim, V.; Mendonça-Júnior, F.J.B.; do Carmo A de Lima, M.; de Moura, R.O.; da Silva-Júnior, E.F.; de Araújo-Júnior, J.X.; de A Dantas, M.D.; de O O Nascimento, E.; Maciel, T.M.S.; de Aquino, T.M.; Figueiredo, I.M.; Santos, J.C.C. Correlation between DNA/HSA-interactions and antimalarial activity of acridine derivatives: Proposing a possible mechanism of action.J. Photochem. Photobiol. B201818916517510.1016/j.jphotobiol.2018.10.01630366283
    [Google Scholar]
  27. AhmedS.A. Al-ShanonA.F. Al-SaffarA.Z. TawangA. Al-ObaidiJ.R. Antiproliferative and cell cycle arrest potentials of 3-O-acetyl-11-keto-β-boswellic acid against MCF-7 cells in vitro.J. Genet. Eng. Biotechnol.20232117510.1186/s43141‑023‑00529‑237393563
    [Google Scholar]
  28. MusciaG.C. BuldainG.Y. AsísS.E. Design, synthesis and evaluation of acridine and fused-quinoline derivatives as potential anti-tuberculosis agents.Eur. J. Med. Chem.20147324324910.1016/j.ejmech.2013.12.01324412719
    [Google Scholar]
  29. AzabH.A. HusseinB.H.M. El-AzabM.F. GomaaM. El-FaloujiA.I. Bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex a new apoptotic agent through Flk-1 down regulation, caspase-3 activation and oligonucleosomes DNA fragmentation.Bioorg. Med. Chem.201321122323410.1016/j.bmc.2012.10.02023200222
    [Google Scholar]
  30. MoharebR.M. IbrahimR.A. Al FaroukF.O. AlwanE.S. Ionic liquid immobilized synthesis of new xantheses derivatives and their antiproliferative, molecular docking and morphological studies.Anticancer. Agents Med. Chem.20242413990100810.2174/011871520629940724032411050538685778
    [Google Scholar]
  31. MoharebR.M. MukhtarS. ParveenH. AbdelazizM.A. AlwanE.S. Anti-proliferative, morphological and molecular docking studies of new thiophene derivatives and their strategy in ionic liquids immobilized reactions.Anticancer. Agents Med. Chem.202424969170810.2174/011871520626230723112210474838321904
    [Google Scholar]
  32. SunderhausJ.D. MartinS.F. Applications of multicomponent reactions to the synthesis of diverse heterocyclic scaffolds.Chemistry20091561300130810.1002/chem.20080214019132705
    [Google Scholar]
  33. JohnS.E. GulatiS. ShankaraiahN. Recent advances in multi-component reactions and their mechanistic insights: A triennium review.Org. Chem. Front.20218154237428710.1039/D0QO01480J
    [Google Scholar]
  34. ZhongY. Arylformylacetonitriles in Multicomponent Reactions Leading to Heterocycles.Eur. J. Org. Chem.2022202248e20220103810.1002/ejoc.202201038
    [Google Scholar]
  35. JavahershenasR. Recent advances in the application of deep eutectic solvents for the synthesis of Spiro heterocyclic scaffolds via multicomponent reactions.J. Mol. Liq.202338512239810.1016/j.molliq.2023.122398
    [Google Scholar]
  36. JabeenT. AslamS. YaseenM. Jawwad SaifM. AhmadM. Al-HussainS.A. ZakiM.E.A. Recent synthetic strategies of medicinally important imidazothiadiazoles.J. Saudi Chem. Soc.202327410167910.1016/j.jscs.2023.101679
    [Google Scholar]
  37. OliveiraG.H.C. RamosL.M. de PaivaR.K.C. PassosS.T.A. SimõesM.M. MachadoF. CorreaJ.R. NetoB.A.D. Synthetic enzyme-catalyzed multicomponent reaction for Isoxazol-5(4 H)-one Syntheses, their properties and biological application; why should one study mechanisms?Org. Biomol. Chem.20211971514153110.1039/D0OB02114H33332518
    [Google Scholar]
  38. KnudsenB.S. GmyrekG.A. InraJ. ScherrD.S. VaughanE.D. NanusD.M. KattanM.W. GeraldW.L. Vande WoudeG.F. High expression of the Met receptor in prostate cancer metastasis to bone.Urology20026061113111710.1016/S0090‑4295(02)01954‑412475693
    [Google Scholar]
  39. HumphreyP.A. ZhuX. ZarnegarR. SwansonP.E. RatliffT.L. VollmerR.T. DayM.L. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma.Am. J. Pathol.199514723863967639332
    [Google Scholar]
  40. RubinJ. BottaroD.P. AaronsonS.A. Hepatocyte growth factor/scatter factor and its receptor, the c-met proto-oncogene product.Biochim. Biophys. Acta Rev. Cancer19931155335737110.1016/0304‑419X(93)90015‑58268192
    [Google Scholar]
  41. OrganS.L. TsaoM.S. An overview of the c-MET signaling pathway.Ther. Adv. Med. Oncol.201131_suppl)(Suppl.S7S1910.1177/175883401142255622128289
    [Google Scholar]
  42. AzgomiN. MokhtaryM. Nano-Fe3O4@SiO2 supported ionic liquid as an efficient catalyst for the synthesis of 1,3-thiazolidin-4-ones under solvent-free conditions.J. Mol. Catal. Chem.2015398586410.1016/j.molcata.2014.11.018
    [Google Scholar]
  43. PeachM.L. TanN. ChoykeS.J. GiubellinoA. AthaudaG. BurkeT.R.Jr NicklausM.C. BottaroD.P. BottaroD.P. Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening.J. Med. Chem.200952494395110.1021/jm800791f19199650
    [Google Scholar]
  44. De BaccoF. LuraghiP. MedicoE. ReatoG. GirolamiF. PereraT. GabrieleP. ComoglioP.M. BoccaccioC. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer.J. Natl. Cancer Inst.2011103864566110.1093/jnci/djr09321464397
    [Google Scholar]
  45. Mariam RajuR. JoyA. J.; Nulgumnalli Manjunathaiah, R.; Justin, A.; Prashantha Kumar, B.R. EGFR as therapeutic target to develop new generation tyrosine kinase inhibitors against breast cancer: A critical review.Results in Chemistry2024710149010.1016/j.rechem.2024.101490
    [Google Scholar]
  46. OtaniT. SuzukiM. TakakuraH. HanaokaH. Synthesis and biological evaluation of EGFR binding peptides for near-infrared photoimmunotherapy.Bioorg. Med. Chem.202410511771710.1016/j.bmc.2024.11771738614014
    [Google Scholar]
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  • Article Type:
    Research Article
Keyword(s): acridine; Cyclohexan-1,3-dione; cytotoxicity; multicomponent; tyrosine kinases; xanthene
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