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2000
Volume 21, Issue 6
  • ISSN: 1573-4064
  • E-ISSN: 1875-6638

Abstract

Background

Over the past ten years, a remarkable number of changes have occurred in the field of cancer drug research. Most anticancer drugs from the first generation work by breaking down DNA, preventing its production, interfering with cell division processes, or attaching to microtubules. The potential use of tryptanthrin as well as its analogues is well documented for anticancer properties.

Objective

To design a novel hybrid of tryptanthrin analogs with expected anticancer activity.

Methods

By changing the C-6 carbonyl position of the tryptanthrin molecule, a set of 72 derivatives of substituted-6-benzylidine-6-indolo[2,1-] quinazoline-12-one was developed. These ligands were screened using Schrodinger Glide extra precision docking against DNA topoisomerase using doxorubicin and teniposide as references to identify their potential anticancer properties. Further, these ligands were subjected to an ADMET study to identify their drug likeliness.

Results

Combined results of molecular docking and ADMET study suggest that out of the total 72 ligands, 6 ligands RC 51, RC 29, RC 42, RC 3, RC 54, and RC 63 were showing very better binding affinity than the natural ligand adenylyl-imidodiphosphate and the two standard reference drugs- doxorubicin and teniposide.

Conclusion

Our computational approach was successful in identifying ligands that are potentially potent topoisomerase inhibitors. These can be tested further using and analysis.

© 2025 Bentham Science Publishers
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2025-10-31

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References

  1. KaurR. ManjalS.K. RawalR.K. KumarK. Recent synthetic and medicinal perspectives of tryptanthrin.Bioorg. Med. Chem.201725174533455210.1016/j.bmc.2017.07.003 28720329
     [Google Scholar]
  2. Rodríguez-RomeroJ.J. Aceves-LaraC.A. SilvaC.F. GschaedlerA. Amaya-DelgadoL. ArrizonJ. 2-Phenylethanol and 2-phenylethylacetate production by nonconventional yeasts using tequila vinasses as a substrate.Biotechnol. Rep.202025e0042010.1016/j.btre.2020.e00420 32025510
     [Google Scholar]
  3. PopovA.M. OsipovA.N. KorepanovaE.A. KrivoshapkoO.N. ShtodaY.P. KlimovichA.A. Study of antioxidant and membranotropic activities of quinazoline alkaloid tryptanthrin using different model systems.Biofizika2015604700707 26394469
     [Google Scholar]
  4. HaoY. GuoJ. WangZ. LiuY. LiY. MaD. WangQ. Discovery of tryptanthrins as novel antiviral and anti-phytopathogenic-fungus agents.J. Agric. Food Chem.202068205586559510.1021/acs.jafc.0c02101 32357298
     [Google Scholar]
  5. KirpotinaL.N. SchepetkinI.A. HammakerD. KuhsA. KhlebnikovA.I. QuinnM.T. Therapeutic effects of tryptanthrin and tryptanthrin-6-oxime in models of rheumatoid arthritis.Front. Pharmacol.202011114510.3389/fphar.2020.01145 32792961
     [Google Scholar]
  6. JahngY. Progress in the studies on tryptanthrin, an alkaloid of history.Arch. Pharm. Res.201336551753510.1007/s12272‑013‑0091‑9 23543631
     [Google Scholar]
  7. HwangJ.M. OhT. KanekoT. UptonA.M. FranzblauS.G. MaZ. Design, synthesis, and structure activity relationship studies of tryptanthrins as antitubercular agents.J. Nat. Prod.201276335436710.1021/np3007167 23360475
     [Google Scholar]
  8. ShangX.F. Morris-NatschkeS.L. YangG.Z. LiuY.Q. GuoX. XuX.S. GotoM. LiJ.C. ZhangJ.Y. LeeK.H. Biologically active quinoline and quinazoline alkaloids part II.Med. Res. Rev.20183851614166010.1002/med.21492 29485730
     [Google Scholar]
  9. Hesse-MacabataJ. MorgnerB. ElsnerP. HiplerU.C. WiegandC. Tryptanthrin promotes keratinocyte and fibroblast responses in vitro after infection with Trichophyton benhamiae DSM6916.Sci. Rep.2020101186310.1038/s41598‑020‑58773‑2 32024909
     [Google Scholar]
  10. MatveevskayaV.V. PavlovD.I. SukhikhT.S. GushchinA.L. IvanovA.Y. TennikovaT.B. SharoykoV.V. BaykovS.V. BenassiE. PotapovA.S. Arene-ruthenium (II) complexes containing 11H-Indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime: Synthesis, characterization, cytotoxicity, and catalytic transfer hydrogenation of aryl ketones.ACS Omega2020519111671117910.1021/acsomega.0c01204 32455240
     [Google Scholar]
  11. TejaC. RamanathanK. NareshK. VidyaR. GomathiK. NawazF.R. Design, synthesis, and biological evaluation of tryptanthrin alkaloids as potential anti-diabetic and anticancer agents.Polycycl. Aromat. Compd.202343187489410.1080/10406638.2021.2021257
     [Google Scholar]
  12. PinheiroD. PineiroM. Seixas de MeloJ.S. Tryptanthrin derivatives as efficient singlet oxygen sensitizers.Photochem. Photobiol. Sci.202221564565810.1007/s43630‑021‑00117‑8 34735707
     [Google Scholar]
  13. YuS. ChernJ. ChenT. ChiuY. ChenH. ChenY. Cytotoxicity and reversal of multidrug resistance by tryptanthrin-derived indoloquinazolines.Acta Pharmacol. Sin.201031225926410.1038/aps.2009.198 20139909
     [Google Scholar]
  14. SridharM. RaviG. ReddyL.K. ReddyP.M. RameshP. RajuA.K. Synthesis of Co(II) metal complexes of tryptanthrin schiff bases, characterization, their biological evaluation, and molecular docking studies.Asian J. Green Chem.20248441456
     [Google Scholar]
  15. ZouY. ZhangG. LiC. LongH. ChenD. LiZ. OuyangG. ZhangW. ZhangY. WangZ. Discovery of tryptanthrin and its derivatives and its activities against NSCLC in vitro via both apoptosis and autophagy pathways.Int. J. Mol. Sci.2023242145010.3390/ijms24021450 36674964
     [Google Scholar]
  16. PopovA. KlimovichA. StyshovaO. MoskovkinaT. ShchekotikhinA. GrammatikovaN. DezhenkovaL. KaluzhnyD. DeriabinP. GerasimenkoA. UdovenkoA. StonikV. Design, synthesis and biomedical evaluation of mostotrin, a new water soluble tryptanthrin derivative.Int. J. Mol. Med.20204641335134610.3892/ijmm.2020.4693 32945360
     [Google Scholar]
  17. YakkalaP.A. PenumalluN.R. ShafiS. KamalA. Prospects of topoisomerase inhibitors as promising anti-cancer agents.Pharmaceuticals202316101456148010.3390/ph16101456 37895927
     [Google Scholar]
  18. HouB. ZhouY. LiW. LiuJ. WangC. Synthesis and evaluation of tryptanthrins as antitumor agents.Tetrahedron20219913245410.1016/j.tet.2021.132454
     [Google Scholar]
  19. LongH. ZhangG. ZhouY. QinL. ZhuD. ChenJ. LiuB. TanH. ChenD. LiZ. LiC. WangZ. A novel tryptanthrin derivative d6 induces apoptosis and DNA damage in non-small-cell lung cancer cells through regulating the EGFR pathway.Anticancer. Agents Med. Chem.202424171275128710.2174/0118715206303721240715042526 39034729
     [Google Scholar]
  20. ZhouX. Recent advances of tryptanthrin and its derivatives as potential anticancer agents.RSC Med. Chem.20241541127114710.1039/D3MD00698K 38665827
     [Google Scholar]
  21. SchepetkinI.A. KarpenkoO.S. KovrizhinaA.R. KirpotinaL.N. KhlebnikovA.I. ChekalS.I. RadudikA.V. ShybinskaM.O. QuinnM.T. Novel tryptanthrin derivatives with selectivity as c–jun n–terminal kinase (JNK) 3 inhibitors.Molecules20232812480610.3390/molecules28124806 37375361
     [Google Scholar]
  22. KimotoT. HinoK. Koya-MiyataS. YamamotoY. TakeuchiM. NishizakiY. MicallefM.J. UshioS. IwakiK. IkedaM. KurimotoM. Cell differentiation and apoptosis of monocytic and promyelocytic leukemia cells (U‐937 and HL‐60) by tryptanthrin, an active ingredient of Polygonum tinctorium Lour.Pathol. Int.200151531532510.1046/j.1440‑1827.2001.01204.x 11422788
     [Google Scholar]
  23. ChanH.L. YipH.Y. MakN.K. LeungK.N. Modulatory effects and action mechanisms of tryptanthrin on murine myeloid leukemia cells.Cell. Mol. Immunol.20096533534210.1038/cmi.2009.44 19887046
     [Google Scholar]
  24. YangS. LiX. HuF. LiY. YangY. YanJ. KuangC. YangQ. Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2,3-dioxygenase with therapeutic activity in Lewis lung cancer (LLC) tumor-bearing mice.J. Med. Chem.201356218321833110.1021/jm401195n 24099220
     [Google Scholar]
  25. BandekarP.P. RoopnarineK.A. ParekhV.J. MitchellT.R. NovakM.J. SindenR.R. Antimicrobial activity of tryptanthrins in Escherichia coli.J. Med. Chem.20105393558356510.1021/jm901847f 20373766
     [Google Scholar]
  26. SeyaK. YamayaA. KamachiS. MurakamiM. KitaharaH. KawakamiJ. OkumuraK. MurakamiM. MotomuraS. FurukawaK.I. 8-Methyltryptanthrin-induced differentiation of P19CL6 embryonal carcinoma cells into spontaneously beating cardiomyocyte-like cells.J. Nat. Prod.20147761413141910.1021/np500108r 24885014
     [Google Scholar]
  27. CatanzaroE. BetariN. ArencibiaJ.M. MontanariS. SissiC. De SimoneA. VassuraI. SantiniA. AndrisanoV. TumiattiV. De VivoM. KryskoD.V. RocchiM.B.L. FimognariC. MilelliA. Targeting topoisomerase II with trypthantrin derivatives: Discovery of 7-((2-(dimethylamino)ethyl)amino)indolo[2,1-b]quinazoline-6,12-dione as an antiproliferative agent and to treat cancer.Eur. J. Med. Chem.202020211250410.1016/j.ejmech.2020.112504 32712536
     [Google Scholar]
  28. TerrynR.J.III GermanH.W. KummererT.M. SindenR.R. BaumJ.C. NovakM.J. Novel computational study on π-stacking to understand mechanistic interactions of Tryptanthrin analogues with DNA.Toxicol. Mech. Methods2014241737910.3109/15376516.2013.859194 24156546
     [Google Scholar]
  29. ChangC.F. HsuY.L. LeeC.Y. WuC.H. WuY.C. ChuangT.H. Isolation and cytotoxicity evaluation of the chemical constituents from Cephalantheropsis gracilis.Int. J. Mol. Sci.20151623980398910.3390/ijms16023980 25686035
     [Google Scholar]
  30. PalabindelaR. GudaR. RameshG. MyadaraveniP. BanothuD. RaviG. KorraR. MekalaH. KasulaM. Novel tryptanthrin hybrids bearing aminothiazoles as potential EGFR inhibitors: Design, synthesis, biological screening, molecular docking studies, and ADME/T predictions.J. Heterocycl. Chem.20225991533155010.1002/jhet.4488
     [Google Scholar]
  31. SeolY. NeumanK.C. The dynamic interplay between DNA topoisomerases and DNA topology.Biophys. Rev.20168Suppl. 110111110.1007/s12551‑016‑0240‑8 28510219
     [Google Scholar]
  32. LeeJ.H. BergerJ.M. Cell cycle-dependent control and roles of DNA topoisomerase II.Genes2019101185910.3390/genes10110859 31671531
     [Google Scholar]
  33. NitissJ.L. Targeting DNA topoisomerase II in cancer chemotherapy.Nat. Rev. Cancer20099533835010.1038/nrc2607 19377506
     [Google Scholar]
  34. StingeleJ. BellelliR. BoultonS.J. Mechanisms of DNA–protein crosslink repair.Nat. Rev. Mol. Cell Biol.201718956357310.1038/nrm.2017.56 28655905
     [Google Scholar]
  35. WeiH. RuthenburgA.J. BechisS.K. VerdineG.L. Nucleotide-dependent domain movement in the ATPase domain of a human type IIA DNA topoisomerase.J. Biol. Chem.200528044370413704710.1074/jbc.M506520200 16100112
     [Google Scholar]
  36. O’BoyleN.M. BanckM. JamesC.A. MorleyC. VandermeerschT. HutchisonG.R. Open babel: An open chemical toolbox.J. Cheminform.2011313310.1186/1758‑2946‑3‑33 21982300
     [Google Scholar]
  37. RoosK. WuC. DammW. ReboulM. StevensonJ.M. LuC. DahlgrenM.K. MondalS. ChenW. WangL. AbelR. FriesnerR.A. HarderE.D. OPLS3e: Extending force field coverage for drug-like small molecules.J. Chem. Theory Comput.20191531863187410.1021/acs.jctc.8b01026 30768902
     [Google Scholar]
  38. ReleaseS. 2018-4: Maestro, version 11.8.New York, NYSchrödinger, LLC2018
     [Google Scholar]
  39. DelgadoJ.L. HsiehC.M. ChanN.L. HiasaH. Topoisomerases as anticancer targets.Biochem. J.2018475237339810.1042/BCJ20160583 29363591
     [Google Scholar]
  40. SkokŽ. ZidarN. KikeljD. IlašJ. Dual inhibitors of human DNA topoisomerase II and other cancer-related targets.J. Med. Chem.202063388490410.1021/acs.jmedchem.9b00726 31592646
     [Google Scholar]
  41. CousinsK.R. ChemDraw Ultra 9.0. CambridgeSoft, 100 CambridgePark Drive, Cambridge, MA 02140. www.cambridgesoft.com. See web site for pricing options.J. Am. Chem. Soc.2005127114115411610.1021/ja0410237
     [Google Scholar]
  42. LipinskiC.A. LombardoF. DominyB.W. FeeneyP.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv. Drug Deliv. Rev.2001461-332610.1016/S0169‑409X(00)00129‑0 11259830
     [Google Scholar]
  43. ZhaoY.H. AbrahamM.H. LeJ. HerseyA. LuscombeC.N. BeckG. SherborneB. CooperI. Rate-limited steps of human oral absorption and QSAR studies.Pharm. Res.200219101446145710.1023/A:1020444330011 12425461
     [Google Scholar]
  44. LipinskiC.A. Lead- and drug-like compounds: The rule-of-five revolution.Drug Discov. Today. Technol.20041433734110.1016/j.ddtec.2004.11.007 24981612
     [Google Scholar]
  45. MosbahH. ChahdouraH. MannaiA. SnoussiM. AouadiK. AbreuR.M.V. BouslamaA. AchourL. SelmiB. Biological activities evaluation of enantiopure isoxazolidine derivatives: In vitro, in vivo and in silico studies.Appl. Biochem. Biotechnol.201918731113113010.1007/s12010‑018‑2868‑2 30167968
     [Google Scholar]
  46. RathodB. PawarS. PuriS. DiwanA. KumarK. Recent advancements and developments in the biological importance of 1,3,5-triazines.ChemistrySelect2024912e20230365510.1002/slct.202303655
     [Google Scholar]
  47. PuriS. YadavT.T. ChouhanM. KumarK. Synthetic and clinical perspectives of evotaz: An overview.Mini Rev. Med. Chem.202424437239010.2174/1389557523666230707151553 37424344
     [Google Scholar]
  48. PawarS. KumawatM.K. KunduM. KumarK. Synthetic and medicinal perspective of antileishmanial agents: An overview.J. Mol. Struct.2023127113397710.1016/j.molstruc.2022.133977
     [Google Scholar]
  49. RathodB. KumarK. Synthetic and medicinal perspective of 1,2,4-triazole as anticancer agents.Chem. Biodivers.20221911e20220067910.1002/cbdv.202200679 36226542
     [Google Scholar]
  50. KonarD. MaruS. KarS. KumarK. Synthesis and clinical development of Palbociclib: An overview.Med. Chem.202218122510.2174/1573406417666201204161243 33280599
     [Google Scholar]
  51. PawarS. KumarK. GuptaM.K. RawalR.K. Synthetic and medicinal perspective of fused-thiazoles as anticancer agents.Anticancer. Agents Med. Chem.202121111379140210.2174/1871520620666200728133017 32723259
     [Google Scholar]
  52. KaurR. KumarK. Synthetic and medicinal perspective of quinolines as antiviral agents.Eur. J. Med. Chem.202121511322011325810.1016/j.ejmech.2021.113220 33609889
     [Google Scholar]
  53. KapoorY. KumarK. Structural and clinical impact of anti-allergy agents: An overview.Bioorg. Chem.20209410335110337510.1016/j.bioorg.2019.103351 31668464
     [Google Scholar]
  54. RathodB. PuriS. JuvaleK. AnsariI. PatelH. BaldaniyaL. KumarK. Synthesis and evaluation of tryptanthrin derivatives as promising anticancer agents: In vitro, in silico, and SAR insights.J. Mol. Struct.2024131113836510.1016/j.molstruc.2024.138365
     [Google Scholar]
  55. PuriS. AhmadI. PatelH. KumarK. JuvaleK. Evaluation of oxindole derivatives as a potential anticancer agent against breast carcinoma cells: In vitro, in silico, and molecular docking study.Toxicol. In vitro20238610551710.1016/j.tiv.2022.105517 36396119
     [Google Scholar]
  56. KumawatM.K. KaurR. KumarK. In-silico prediction of novel fused quinazoline based topoisomerase inhibitors as anticancer agents.Med. Chem.202319543144410.2174/1573406418666221012161111 36237156
     [Google Scholar]
/content/journals/mc/10.2174/0115734064334604241014024205
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In silico Study of Novel Tryptanthrin-Based Topoisomerase Inhibitors
Med. Chem. 21, 516 (2025); https://doi.org/10.2174/0115734064334604241014024205
/content/journals/mc/10.2174/0115734064334604241014024205
/content/journals/mc/10.2174/0115734064334604241014024205
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  • Article Type:     Research Article
Keyword(s): antitumor; ATPase domain; glide extra precision docking; molinspiration; pharmacokinetics; topoisomerase IIα; Tryptanthrin

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