Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Letters in Drug Design & Discovery
  4. Fast Track Articles
  5. Fast Track Article
image of Synthesis of New Xanthene and Acridine Derivatives from Cyclohexan-1,3-dione and the Study of their Antiproliferative Activities

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.

Method

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.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/lddd/10.2174/0115701808336532241009105320
2024-10-29
2025-04-15

  • From This Site

    /content/journals/lddd/10.2174/0115701808336532241009105320
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Arbabi Jam S. Sarrafi Y. Maleki B. Immobilization of ionic liquid–triethanolammonium bicarbonate on magnetic nanoparticles as an efficient catalyst for knovenegel condensation. Polycycl. Aromat. Compd. 2024 44 7 4364 4375 10.1080/10406638.2023.2247129
    [Google Scholar]
  2. Abu Zarin M.A. Zainol M.M. Ramli N.A.S. Amin N.A.S. Zeolite immobilized ionic liquid as an effective catalyst for conversion of biomass derivatives to levulinic acid. Molecular Catalysis 2022 528 112506 10.1016/j.mcat.2022.112506
    [Google Scholar]
  3. Jahanbakhshi A. Farahi M. 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. 2022 15 12 104311 10.1016/j.arabjc.2022.104311
    [Google Scholar]
  4. Paterson R. Alharbi A.A. Wills C. Dixon C. Šiller L. Chamberlain T.W. Griffiths A. Collins S.M. Wu K. Simmons M.D. Bourne R.A. Lovelock K.R.J. Seymour J. Knight J.G. Doherty S. Heteroatom modified polymer immobilized ionic liquid stabilized ruthenium nanoparticles: Efficient catalysts for the hydrolytic evolution of hydrogen from sodium borohydride. Molecul. Catal. 2022 528 112476 10.1016/j.mcat.2022.112476
    [Google Scholar]
  5. Wang L. Lu J. Wang Y. Wang H. Wang J. Ren T. 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. 2023 1271 133973 10.1016/j.molstruc.2022.133973
    [Google Scholar]
  6. Elyasi Z. Ghomi J.S. Najafi G.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. 2021 75 105614 10.1016/j.ultsonch.2021.105614 34111724
    [Google Scholar]
  7. Wiredu B. Amarasekara A.S. Synthesis of a silica-immobilized Brönsted acidic ionic liquid catalyst and hydrolysis of cellulose in water under mild conditions. Catal. Commun. 2014 48 41 44 10.1016/j.catcom.2014.01.021
    [Google Scholar]
  8. Sun J. Yang J. Li S. Xu X. Basic ionic liquid immobilized oxides as heterogeneous catalyst for biodiesel synthesis from waste cooking oil. Catal. Commun. 2016 83 35 38 10.1016/j.catcom.2016.05.002
    [Google Scholar]
  9. Li J. Ni H. Zhang W. Lai Z. Jin H. Zeng L. Cui S. A multicomponent reaction for modular assembly of indole-fused heterocycles. Chem. Sci. (Camb.) 2024 15 14 5211 5217 10.1039/D4SC00522H 38577354
    [Google Scholar]
  10. Zeleke D. Damena T. Advance in green synthesis of pharmacological important heterocycles using multicomponent reactions and magnetic nanocatalysts (MNCs). Resul. Chem. 2024 7 101283 10.1016/j.rechem.2023.101283
    [Google Scholar]
  11. Li J. Gu A. Nong X.M. Zhai S. Yue Z.Y. Li M.Y. Liu Y. Six‐membered aromatic nitrogen heterocyclic anti‐tumor agents: Synthesis and applications. Chem. Rec. 2023 23 12 e202300293 10.1002/tcr.202300293 38010365
    [Google Scholar]
  12. Goodell J.R. Madhok A.A. Hiasa H. Ferguson D.M. Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity. Bioorg. Med. Chem. 2006 14 16 5467 5480 10.1016/j.bmc.2006.04.044 16713270
    [Google Scholar]
  13. Chibale K. Visser M. van Schalkwyk D. Smith P.J. Saravanamuthu A. Fairlamb A.H. Exploring the potential of xanthene derivatives as trypanothione reductase inhibitors and chloroquine potentiating agents. Tetrahedron 2003 59 13 2289 2296 10.1016/S0040‑4020(03)00240‑0
    [Google Scholar]
  14. Kumar A. Parveen M. Shahab A.A. Nami S.A. Azam M. Ansari M.S. Farooq I. Alam M. 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. 2024 28 101807 10.1016/j.jscs.2024.101807
    [Google Scholar]
  15. Banerjee A.G. Kothapalli L.P. Sharma P.A. Thomas A.B. Nanda R.K. Shrivastava S.K. Khatanglekar V.V. A facile microwave assisted one pot synthesis of novel xanthene derivatives as potential anti-inflammatory and analgesic agents. Arab. J. Chem. 2016 9 S480 S489 10.1016/j.arabjc.2011.06.001
    [Google Scholar]
  16. Hafez H.N. Hegab M.I. Ahmed-Farag I.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. 2008 18 4538 4543 10.1016/j.bmcl.2008.07.042
    [Google Scholar]
  17. Ren Y. Ruan Y. Cheng B. Li L. Liu J. Fang Y. Chen J. Design, synthesis and biological evaluation of novel acridine and quinoline derivatives as tubulin polymerization inhibitors with anticancer activities. Bioorg. Med. Chem. 2021 46 116376 10.1016/j.bmc.2021.116376 34455231
    [Google Scholar]
  18. Dutta A.K. Gogoi P. Saikia S. Borah R. 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. 2017 225 585 591 10.1016/j.molliq.2016.11.112
    [Google Scholar]
  19. Wan Y. Zhang X.X. Wang C. Zhao L. L.L.; Chen, L.F.; Liu, G.X.; Huang, S.; Yue, S.; Zhang, W.L.; Wu, H. The first example of glucose-containingBrønsted acid synthesis and catalysis: Efficient synthesis of tetrahydrobenzo[α]xanthens and tetrahydrobenzo[α]acridines in water. Tetrahedron 2013 69 3947 3950 10.1016/j.tet.2013.03.029
    [Google Scholar]
  20. Le Bris M-T. Mugnier J. Bourson J. Valeur B. Spectral properties of a new flourescent dye emitting in the red: A benzoxazinone derivative. Chem. Phys. Lett. 1984 106 1-2 124 127 10.1016/0009‑2614(84)87024‑4
    [Google Scholar]
  21. Yin W. Zhu H. Wang R. A sensitive and selective fluorescence probe based fluorescein for detection of hypochlorous acid and its application for biological imaging. Dyes Pigments 2014 107 127 132 10.1016/j.dyepig.2014.03.012
    [Google Scholar]
  22. Arnoczky S.P. Lavagnino M. Whallon J.H. Hoonjan A. In situ cell nucleus deformation in tendons under tensile load; a morphological analysis using confocal laser microscopy. J. Orthop. Res. 2002 20 1 29 35 10.1016/S0736‑0266(01)00080‑8 11853087
    [Google Scholar]
  23. Li M.Y. Zhai S. Nong X.M. Gu A. Li J. Lin G.Q. Liu Y. Trisubstituted alkenes featuring aryl groups: stereoselective synthetic strategies and applications. Sci. China Chem. 2023 66 5 1261 1287 10.1007/s11426‑022‑1515‑5
    [Google Scholar]
  24. Cui Z. Li X. Li L. Zhang B. Gao C. Chen Y. Tan C. Liu H. Xie W. Yang T. Jiang Y. Design, synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment. Bioorg. Med. Chem. 2016 24 2 261 269 10.1016/j.bmc.2015.12.011 26707846
    [Google Scholar]
  25. Williams D. Kocerha J. Aiken K. Seymour A.M. Blount G. Douglas D. Abstract 1923 anti-cancer activity of acridine derivatives in lung and prostate cancer cells. J. Biol. Chem. 2024 300 3 106109 10.1016/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. B 2018 189 165 175 10.1016/j.jphotobiol.2018.10.016 30366283
    [Google Scholar]
  27. Ahmed S.A. Al-Shanon A.F. Al-Saffar A.Z. Tawang A. Al-Obaidi J.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. 2023 21 1 75 10.1186/s43141‑023‑00529‑2 37393563
    [Google Scholar]
  28. Muscia G.C. Buldain G.Y. Asís S.E. Design, synthesis and evaluation of acridine and fused-quinoline derivatives as potential anti-tuberculosis agents. Eur. J. Med. Chem. 2014 73 243 249 10.1016/j.ejmech.2013.12.013 24412719
    [Google Scholar]
  29. Azab H.A. Hussein B.H.M. El-Azab M.F. Gomaa M. El-Falouji A.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. 2013 21 1 223 234 10.1016/j.bmc.2012.10.020 23200222
    [Google Scholar]
  30. Mohareb R.M. Ibrahim R.A. Al Farouk F.O. Alwan E.S. Ionic liquid immobilized synthesis of new xantheses derivatives and their antiproliferative, molecular docking and morphological studies. Anticancer. Agents Med. Chem. 2024 24 13 990 1008 10.2174/0118715206299407240324110505 38685778
    [Google Scholar]
  31. Mohareb R.M. Mukhtar S. Parveen H. Abdelaziz M.A. Alwan E.S. Anti-proliferative, morphological and molecular docking studies of new thiophene derivatives and their strategy in ionic liquids immobilized reactions. Anticancer. Agents Med. Chem. 2024 24 9 691 708 10.2174/0118715206262307231122104748 38321904
    [Google Scholar]
  32. Sunderhaus J.D. Martin S.F. Applications of multicomponent reactions to the synthesis of diverse heterocyclic scaffolds. Chemistry 2009 15 6 1300 1308 10.1002/chem.200802140 19132705
    [Google Scholar]
  33. John S.E. Gulati S. Shankaraiah N. Recent advances in multi-component reactions and their mechanistic insights: A triennium review. Org. Chem. Front. 2021 8 15 4237 4287 10.1039/D0QO01480J
    [Google Scholar]
  34. Zhong Y. Arylformylacetonitriles in Multicomponent Reactions Leading to Heterocycles. Eur. J. Org. Chem. 2022 2022 48 e202201038 10.1002/ejoc.202201038
    [Google Scholar]
  35. Javahershenas R. Recent advances in the application of deep eutectic solvents for the synthesis of Spiro heterocyclic scaffolds via multicomponent reactions. J. Mol. Liq. 2023 385 122398 10.1016/j.molliq.2023.122398
    [Google Scholar]
  36. Jabeen T. Aslam S. Yaseen M. Jawwad Saif M. Ahmad M. Al-Hussain S.A. Zaki M.E.A. Recent synthetic strategies of medicinally important imidazothiadiazoles. J. Saudi Chem. Soc. 2023 27 4 101679 10.1016/j.jscs.2023.101679
    [Google Scholar]
  37. Oliveira G.H.C. Ramos L.M. de Paiva R.K.C. Passos S.T.A. Simões M.M. Machado F. Correa J.R. Neto B.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. 2021 19 7 1514 1531 10.1039/D0OB02114H 33332518
    [Google Scholar]
  38. Knudsen B.S. Gmyrek G.A. Inra J. Scherr D.S. Vaughan E.D. Nanus D.M. Kattan M.W. Gerald W.L. Vande Woude G.F. High expression of the Met receptor in prostate cancer metastasis to bone. Urology 2002 60 6 1113 1117 10.1016/S0090‑4295(02)01954‑4 12475693
    [Google Scholar]
  39. Humphrey P.A. Zhu X. Zarnegar R. Swanson P.E. Ratliff T.L. Vollmer R.T. Day M.L. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am. J. Pathol. 1995 147 2 386 396 7639332
    [Google Scholar]
  40. Rubin J. Bottaro D.P. Aaronson S.A. Hepatocyte growth factor/scatter factor and its receptor, the c-met proto-oncogene product. Biochim. Biophys. Acta Rev. Cancer 1993 1155 3 357 371 10.1016/0304‑419X(93)90015‑5 8268192
    [Google Scholar]
  41. Organ S.L. Tsao M.S. An overview of the c-MET signaling pathway. Ther. Adv. Med. Oncol. 2011 3 1_suppl Suppl. S7 S19 10.1177/1758834011422556 22128289
    [Google Scholar]
  42. Azgomi N. Mokhtary M. 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. 2015 398 58 64 10.1016/j.molcata.2014.11.018
    [Google Scholar]
  43. Peach M.L. Tan N. Choyke S.J. Giubellino A. Athauda G. Burke T.R. Jr Nicklaus M.C. Bottaro D.P. Bottaro D.P. Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening. J. Med. Chem. 2009 52 4 943 951 10.1021/jm800791f 19199650
    [Google Scholar]
  44. De Bacco F. Luraghi P. Medico E. Reato G. Girolami F. Perera T. Gabriele P. Comoglio P.M. Boccaccio C. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J. Natl. Cancer Inst. 2011 103 8 645 661 10.1093/jnci/djr093 21464397
    [Google Scholar]
  45. Mariam Raju R. Joy A 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 Chemistry 2024 7 101490 10.1016/j.rechem.2024.101490
    [Google Scholar]
  46. Otani T. Suzuki M. Takakura H. Hanaoka H. Synthesis and biological evaluation of EGFR binding peptides for near-infrared photoimmunotherapy. Bioorg. Med. Chem. 2024 105 117717 10.1016/j.bmc.2024.117717 38614014
    [Google Scholar]
/content/journals/lddd/10.2174/0115701808336532241009105320
Loading
Synthesis of New Xanthene and Acridine Derivatives from Cyclohexan-1,3-dione and the Study of their Antiproliferative Activities
Bentham Science Publishers ; https://doi.org/10.2174/0115701808336532241009105320
/content/journals/lddd/10.2174/0115701808336532241009105320
/content/journals/lddd/10.2174/0115701808336532241009105320
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: tyrosine kinases ; xanthene ; cytotoxicity ; Cyclohexan-1,3-dione ; multicomponent ; acridine

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test