Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents)
  4. Fast Track Articles
  5. Fast Track Article
image of Design, Synthesis, and Molecular Docking Studies of Indolo[3,2-c]Quinolines as Topoisomerase Inhibitors

Abstract

Background

The tetracyclic indoloquinoline ring system has attracted considerable interest in the recent past due to its broad spectrum of biological activities and its binding to various types of nucleic acids.

Objective

This study aims to elucidate their interactions with DNA and their effects on topoisomerases (TOPO) I and II.

Methods

Several compounds derived from 6-amino-11H-indolo[3,2-c]quinoline with diverse groups on the quinoline ring have been successfully synthesized according to a previously established protocol where all the synthesized indolo[3,2-c]quinoline derivatives were evaluated against A549, HCT-116, BALB/3T3, and MV4-11 cell lines using MTT (3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl- tetrazolium bromide) assay. These derivatives were then screened for their topo I and II inhibitory activities.

Results

The tested compounds were more effective at killing MV4-11 leukemia cells than the standard cancer drug cisplatin, as shown by the fact that their IC values were less than 0.9 μM. On the other hand, cisplatin revealed an IC value of 2.36 μM. Moreover, they exhibited inhibitory activity against both Topoisomerase (Topo) I and II. The most potent compound, , demonstrated a suppressive impact on topoisomerase I, with an IC value of 2.9 μM compared to the positive control Camptothecin (IC 1.64 μM) and compound displayed remarkable topoisomerase II inhibitory activity with an IC of 6.82 μM compared to the positive control Doxorubicin (IC 6.49 μM). The cell cycle study for compounds and revealed that cell cycle arrest occurred at the G1/S and S phases, respectively. Compounds and showed a high selectivity index, which suggests that they could be used to develop low-toxicity chemotherapeutic agents.

Conclusion

The results of this study demonstrate that compounds and can be considered promising candidates for further anti-cancer drug development, which might be related to inhibiting TOPO I and TOPO II activities.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/acamc/10.2174/0118715206360700241219065917
2025-02-03
2025-03-26

  • From This Site

    /content/journals/acamc/10.2174/0118715206360700241219065917
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Bray F. Laversanne M. Sung H. Ferlay J. Siegel R.L. Soerjomataram I. Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024 74 3 229 263 10.3322/caac.21834 38572751
    [Google Scholar]
  2. Soerjomataram I. Bray F. Planning for tomorrow: Global cancer incidence and the role of prevention 2020–2070. Nat. Rev. Clin. Oncol. 2021 18 10 663 672 10.1038/s41571‑021‑00514‑z 34079102
    [Google Scholar]
  3. El Sayed I.E. Synthesis, Nanoformulations and In-vitro anticancer activity of N-substituted side chain neocryptolepine scaffolds. Molecuoles 2022 27 3
    [Google Scholar]
  4. Selvam T.P. Karthick V. Kumar P.V. Ali M.A. Synthesis and structure-activity relationship study of 2-(substituted benzylidene)-7-(4-fluorophenyl)-5-(furan-2-yl)-2H-thiazolo[3,2-a]pyrimidin-3(7H)-one derivatives as anticancer agents. Drug Discov. Ther. 2012 6 4 198 204 10.5582/ddt.2012.v6.4.198 23006990
    [Google Scholar]
  5. Akkachairin B. Tummatorn J. Khamsuwan N. Thongsornkleeb C. Ruchirawat S. Domino N 2 -extrusion–cyclization of alkynylarylketone derivatives for the synthesis of indoloquinolines and carbocycle-fused quinolines. J. Org. Chem. 2018 83 18 11254 11268 10.1021/acs.joc.8b01851 30084635
    [Google Scholar]
  6. Aksenov A.V. Aksenov D.A. Orazova N.A. Aksenov N.A. Griaznov G.D. De Carvalho A. Kiss R. Mathieu V. Kornienko A. Rubin M. One-pot, three-component assembly of indoloquinolines: Total synthesis of isocryptolepine. J. Org. Chem. 2017 82 6 3011 3018 10.1021/acs.joc.6b03084 28253622
    [Google Scholar]
  7. Parvatkar P.T. Parameswaran P.S. Indoloquinolines: Possible biogenesis from common indole precursors and their synthesis using domino strategies. Curr. Org. Synth. 2015 13 1 58 72 10.2174/1570179412666150511224648
    [Google Scholar]
  8. Wright C.W. Addae-Kyereme J. Breen A.G. Brown J.E. Cox M.F. Croft S.L. Gökçek Y. Kendrick H. Phillips R.M. Pollet P.L. Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents. J. Med. Chem. 2001 44 19 3187 3194 10.1021/jm010929+ 11543688
    [Google Scholar]
  9. Onyeibor O. Croft S.L. Dodson H.I. Feiz-Haddad M. Kendrick H. Millington N.J. Parapini S. Phillips R.M. Seville S. Shnyder S.D. Taramelli D. Wright C.W. Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action. J. Med. Chem. 2005 48 7 2701 2709 10.1021/jm040893w 15801861
    [Google Scholar]
  10. Wang N. Structural modifications of nature-inspired indoloquinolines: A mini review of their potential antiproliferative activity. Molecules 2019 24 11 10.3390/molecules24112121
    [Google Scholar]
  11. Ibrahim E.S. Montgomerie A.M. Sneddon A.H. Proctor G.R. Green B. Synthesis of indolo[3,2-c]quinolines and indolo[3,2-d]benzazepines and their interaction with DNA. Eur. J. Med. Chem. 1988 23 2 183 188 10.1016/0223‑5234(88)90192‑4
    [Google Scholar]
  12. Marquez V.E. Cranston J.W. Ruddon R.W. Kier L.B. Burckhalter J.H. Mechanism of action of amodiaquine. Synthesis of its indoloquinoline analog. J. Med. Chem. 1972 15 1 36 39 10.1021/jm00271a010 4550134
    [Google Scholar]
  13. Lu W.J. Świtalska M. Wang L. Yonezawa M. El-Sayed I.E-T. Wietrzyk J. Inokuchi T. In vitros antiproliferative activity of 11-aminoalkylamino-substituted 5H-indolo[2,3-b]quinolines; Improving activity of neocryptolepines by installation of ester substituent. Med. Chem. Res. 2013 22 9 4492 4504 10.1007/s00044‑012‑0443‑x
    [Google Scholar]
  14. Ahmed A.A.S. Awad H.M. El-Sayed I.E.T. El Gokha A.A. Synthesis and antiproliferative activity of new hybrids bearing neocryptolepine, acridine and α-aminophosphonate scaffolds. J. Indian Chem. Soc. 2020 17 5 1211 1221 10.1007/s13738‑019‑01849‑2
    [Google Scholar]
  15. Fan M. Screening for natural inhibitors of human topoisomerases from medicinal plants with bio-affinity ultrafiltration and LC–MS. Phytochem. Rev. 2020 19 5 1231 1261 10.1007/s11101‑019‑09635‑x
    [Google Scholar]
  16. Singh S. Pandey V.P. Yadav K. Yadav A. Dwivedi U.N. Natural products as anti-cancerous therapeutic molecules targeted towards topoisomerases. Curr. Protein Pept. Sci. 2020 21 11 1103 1142 10.2174/1389203721666200918152511 32951576
    [Google Scholar]
  17. Nofal A.E. Elmongy E.I. Hassan E.A. Tousson E. Ahmed A.A.S. El Sayed I.E.T. Binsuwaidan R. Sakr M. Impact of synthesized indoloquinoline analog to isolates from Cryptolepis sanguinolenta on tumor growth inhibition and hepatotoxicity in ehrlich solid tumor-bearing female mice. Cells 2023 12 7 1024 10.3390/cells12071024 37048097
    [Google Scholar]
  18. Liang X. A comprehensive review of topoisomerase inhibitors as anticancer agents in the past decade. Europ. J. Med. Chem. 2019 171 129 168 10.1016/j.ejmech.2019.03.034
    [Google Scholar]
  19. Wang J.C. Cellular roles of DNA topoisomerases: A molecular perspective. Nat. Rev. Mol. Cell Biol. 2002 3 6 430 440 10.1038/nrm831 12042765
    [Google Scholar]
  20. Badr M. Elmongy E.I. Elkhateeb D. Moemen Y.S. Khalil A. Ali H. Binsuwaidan R. Awadallah F. El Sayed I.E.T. In silico and in vitros investigation of cytotoxicity and apoptosis of acridine/sulfonamide hybrids targeting topoisomerases I and II. Pharmaceuticals 2024 17 11 1487 10.3390/ph17111487
    [Google Scholar]
  21. Khadka D.B. Cho W.J. Topoisomerase inhibitors as anticancer agents: A patent update. Expert Opin. Ther. Pat. 2013 23 8 1033 1056 10.1517/13543776.2013.790958 23611704
    [Google Scholar]
  22. Wang N. Świtalska M. Wu M.Y. Imai K. Ngoc T.A. Pang C.Q. Wang L. Wietrzyk J. Inokuchi T. Synthesis and in vitros cytotoxic effect of 6-amino-substituted 11H- and 11Me-indolo[3,2-c]quinolines. Eur. J. Med. Chem. 2014 78 314 323 10.1016/j.ejmech.2014.03.038 24686018
    [Google Scholar]
  23. Skehan P. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 1990 82 13 1107 1112
    [Google Scholar]
  24. Quadruplex G. Hu M. Lin J. New dibenzoquinoxalines inhibit triple-negative breast cancer growth by dual targeting of topoisomerase 1 and the c-MYC G-quadruplex. J. Med. Chem. 2021 64 10 6720 6729 10.1021/acs.jmedchem.0c02202
    [Google Scholar]
  25. Eissa I.H. El-Naggar A.M. El-Sattar N.E.A.A. Youssef A.S.A. Design and discovery of novel quinoxaline derivatives as dual DNA intercalators and topoisomerase II inhibitors. Anticancer. Agents Med. Chem. 2018 18 2 195 209 10.2174/1871520617666170710182405 28699490
    [Google Scholar]
  26. Turky A. Bayoumi A.H. Ghiaty A. El-Azab A.S. A-M Abdel-Aziz A. Abulkhair H.S. Design, synthesis, and antitumor activity of novel compounds based on 1,2,4-triazolophthalazine scaffold: Apoptosis-inductive and PCAF-inhibitory effects. Bioorg. Chem. 2020 101 104019 10.1016/j.bioorg.2020.104019 32615465
    [Google Scholar]
  27. Andree H.A. Reutelingsperger C.P. Hauptmann R. Hemker H.C. Hermens W.T. Willems G.M. Binding of vascular anticoagulant α (VAC α) to planar phospholipid bilayers. J. Biol. Chem. 1990 265 9 4923 4928 10.1016/S0021‑9258(19)34062‑1 2138622
    [Google Scholar]
  28. Shum J. Leung P.K.K. Lo K.K.W. Luminescent Ruthenium(II) polypyridine complexes for a wide variety of biomolecular and cellular applications. Inorg. Chem. 2019 58 4 2231 2247 10.1021/acs.inorgchem.8b02979 30693762
    [Google Scholar]
  29. Segun P.A. Ogbole O.O. Ismail F.M.D. Nahar L. Evans A.R. Ajaiyeoba E.O. Sarker S.D. Resveratrol derivatives from Commiphora africana ( A. Rich. ) Endl. display cytotoxicity and selectivity against several human cancer cell lines. Phytother. Res. 2019 33 1 159 166 10.1002/ptr.6209 30346066
    [Google Scholar]
  30. Sutejo I.R. Putri H. Meiyanto E. The selectivity of ethanolic extract of buah makassar (Brucea javanica) on metastatic breast cancer cells. J. Agromed. Med. Sci. 1970 2 1 1 6 10.19184/ams.v2i1.2422
    [Google Scholar]
  31. Butt S.S. Badshah Y. Shabbir M. Rafiq M. Molecular docking using chimera and autodock vina software for nonbioinformaticians. JMIR Bioinform. Biotechnol. 2020 1 1 e14232 10.2196/14232 38943236
    [Google Scholar]
  32. Daina A. Michielin O. Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017 7 1 42717 10.1038/srep42717 28256516
    [Google Scholar]
  33. Wenzel E.S. Singh A.T.K. Cell-cycle checkpoints and aneuploidy on the path to cancer. In Vivo 2018 32 1 1 5 10.21873/invivo.11197 29275292
    [Google Scholar]
  34. Elbastawesy M.A.I. Aly A.A. Ramadan M. Elshaier Y.A.M.M. Youssif B.G.M. Brown A.B. El-Din A Abuo-Rahma G. Novel pyrazoloquinolin-2-ones: Design, synthesis, docking studies, and biological evaluation as antiproliferative EGFR-TK inhibitors. Bioorg. Chem. 2019 90 103045 10.1016/j.bioorg.2019.103045 31212178
    [Google Scholar]
  35. Da’i M. Meilinasary K.A. Suhendi A. Haryanti S. Selectivity index of alpinia galanga extract and 1′-acetoxychavicol acetate on cancer cell lines. Indones. J. Cancer Chemoprevent. 2019 10 2 95 10.14499/indonesianjcanchemoprev10iss2pp95‑100
    [Google Scholar]
  36. Staker B.L. Hjerrild K. Feese M.D. Behnke C.A. Burgin A.B. Jr Stewart L. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl. Acad. Sci. USA 2002 99 24 15387 15392 10.1073/pnas.242259599 12426403
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206360700241219065917
Loading
Design, Synthesis, and Molecular Docking Studies of Indolo[3,2-c]Quinolines as Topoisomerase Inhibitors
Bentham Science Publishers ; https://doi.org/10.2174/0118715206360700241219065917
/content/journals/acamc/10.2174/0118715206360700241219065917
/content/journals/acamc/10.2174/0118715206360700241219065917
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Research Article
Keywords: anticancer agents ; apoptosis ; topoisomerase inhibitors ; molecular docking ; Indoloquinoline

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