Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Letters in Drug Design & Discovery
  4. Volume 21, Issue 17
  5. Article
Volume 21, Issue 17
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

Cancer represents the major health problem faced by the population of the world, remaining one of the main causes of death. Hence, the development of new targeted antitumor drugs with high efficacy and lower toxicity is still needed.

Objective

As a continuation of our work to discover new molecules with cytotoxic properties, two heterocyclic scaffolds, namely indolizine, and indazole, were combined in the same molecule, aiming to improve the bioactivity. This article focused on the synthesis, characterization, and biological evaluation of a series of new indazole-indolizine hybrid compounds.

Methods

The biological potential of the synthesized compounds was investigated against the human farnesyltransferase enzyme and NCI 60 tumor cell lines panel. While the farnesyltransferase inhibitory activity was modest, a very good antiproliferative action was observed for compound , which, at a concentration of 10 µM, inhibited the growth of 20 types of cancer cells by more than 50% and showed cytotoxic action against the ovarian cancer cell line OVCAR-4.

Results

A series of novel indazole-indolizine hybrids were synthesized a [3+2] cycloaddition reaction, fully characterized and biologically evaluated for antitumor potential.

Conclusion

Compound could be a promising starting point in the development of new antitumoral agents. Further biological investigations will be performed to identify the biological target of the compounds. Moreover, different synthetic strategies to introduce new substituents on the indolizine core will be addressed.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/lddd/10.2174/0115701808323543241018053705
2024-10-21
2025-04-23

  • From This Site

    /content/journals/lddd/10.2174/0115701808323543241018053705
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. ZhuJ. JiangX. LuoX. ZhaoR. LiJ. CaiH. YeX.Y. BaiR. XieT. Combination of chemotherapy and gaseous signaling molecular therapy: Novel β‐elemene nitric oxide donor derivatives against leukemia.Drug Dev. Res.202384471873510.1002/ddr.22051 36988106
     [Google Scholar]
  2. LuY. LiJ. LiuY. ZhuL. XiaoS. BaiM. ChenD. XieT. Bi-enzyme competition based on ZIF-67 co-immobilization for real-time monitoring of exocellular ATP.Mikrochim. Acta202319027110.1007/s00604‑023‑05652‑y 36695915
     [Google Scholar]
  3. MushtaqA. WuP. NaseerM.M. Recent drug design strategies and identification of key heterocyclic scaffolds for promising anticancer targets.Pharmacol. Ther.202425410857910.1016/j.pharmthera.2023.108579 38160914
     [Google Scholar]
  4. ZuoW. ZuoL. GengX. LiZ. WangL. Photoinduced C–H heteroarylation of enamines via quadruple cleavage of CF2 Br2.Org. Chem. Front.202310246112611610.1039/D3QO01474F
     [Google Scholar]
  5. ZhangL. ShiH. TanX. JiangZ. WangP. QinJ. Ten-gram-scale mechanochemical synthesis of ternary lanthanum coordination polymers for antibacterial and antitumor activities.Front Chem.20221089832410.3389/fchem.2022.898324 35774860
     [Google Scholar]
  6. DaiJ. GaoJ. DongH. Prognostic relevance and validation of ARPC1A in the progression of low-grade glioma.Aging (Albany NY)20241614111621118410.18632/aging.205952 39012280
     [Google Scholar]
  7. PuriS. SawantS. JuvaleK. A comprehensive review on the indazole based derivatives as targeted anticancer agents.J. Mol. Struct.2023128413532710.1016/j.molstruc.2023.135327
     [Google Scholar]
  8. CaoY. YangY. Ampomah-WirekoM. Obaid Arhema FrejatF. ZhaiH. ZhangS. WangH. YangP. YuanQ. WuG. WuC. Novel indazole skeleton derivatives containing 1,2,3-triazole as potential anti-prostate cancer drugs.Bioorg. Med. Chem. Lett.20226412865410.1016/j.bmcl.2022.128654 35259487
     [Google Scholar]
  9. XiaM. YuL. YanZ. WangY. ZhangL. MiaoG. LiS. FTase inhibitors and cancer: Prospects for use in targeted therapies.Med. Chem. Res.2024331213510.1007/s00044‑023‑03171‑2
     [Google Scholar]
  10. ZhangS.G. LiangC.G. ZhangW.H. Recent advances in indazole-containing derivatives: Synthesis and biological perspectives.Molecules20182311278310.3390/molecules23112783 30373212
     [Google Scholar]
  11. DongJ. ZhangQ. WangZ. HuangG. LiS. Recent advances in the development of indazole‐based anticancer agents.ChemMedChem201813151490150710.1002/cmdc.201800253 29863292
     [Google Scholar]
  12. WanY. HeS. LiW. TangZ. Indazole derivatives: Promising anti-tumor agents.Anticancer. Agents Med. Chem.20191891228123410.2174/1871520618666180510113822 29745343
     [Google Scholar]
  13. GaikwadD.D. ChapolikarA.D. DevkateC.G. WaradK.D. TayadeA.P. PawarR.P. DombA.J. Synthesis of indazole motifs and their medicinal importance: An overview.Eur. J. Med. Chem.20159070773110.1016/j.ejmech.2014.11.029 25506810
     [Google Scholar]
  14. DenyaI. MalanS.F. JoubertJ. Indazole derivatives and their therapeutic applications: A patent review (2013-2017).Expert Opin. Ther. Pat.201828644145310.1080/13543776.2018.1472240 29718740
     [Google Scholar]
  15. PalD. SongI. Dashrath WarkadS. SongK. Seong YeomG. SahaS. ShindeP.B. Balasaheb NimseS. Indazole-based microtubule-targeting agents as potential candidates for anticancer drugs discovery.Bioorg. Chem.202212210573510.1016/j.bioorg.2022.105735 35298962
     [Google Scholar]
  16. QinJ. ChengW. DuanY.T. YangH. YaoY. Indazole as a privileged scaffold: The derivatives and their therapeutic applications.Anticancer. Agents Med. Chem.202121783986010.2174/1871520620999200818160350 32819234
     [Google Scholar]
  17. ShangC. HouY. MengT. ShiM. CuiG. The anticancer activity of indazole compounds: A mini review.Curr. Top. Med. Chem.202121536337610.2174/1568026620999201124154231 33238856
     [Google Scholar]
  18. DawoodK.M. AbbasA.A. Inhibitory activities of indolizine derivatives: A patent review.Expert Opin. Ther. Pat.202030969571410.1080/13543776.2020.1798402 32684068
     [Google Scholar]
  19. RamalakshmiN. AmuthalakshmiS. YamunaR. Anton SmithA. ArunkumarS. Indolizine-A privileged biological scaffold.Pharma Chem.2021136069
     [Google Scholar]
  20. SinghG.S. MmatliE.E. Recent progress in synthesis and bioactivity studies of indolizines.Eur. J. Med. Chem.201146115237525710.1016/j.ejmech.2011.08.042 21937153
     [Google Scholar]
  21. LucescuL. GhinetA. BeleiD. RigoB. DuboisJ. BîcuE. Discovery of indolizines containing triazine moiety as new leads for the development of antitumoral agents targeting mitotic events.Bioorg. Med. Chem. Lett.201525183975397910.1016/j.bmcl.2015.07.025 26227778
     [Google Scholar]
  22. LeeY. JoshiD.R. NamkungW. KimI. Generation of a poly-functionalized indolizine scaffold and its anticancer activity in pancreatic cancer cells.Bioorg. Chem.202212610587710.1016/j.bioorg.2022.105877 35636126
     [Google Scholar]
  23. AksenovA.V. ArutiunovN.A. KirilovN.K. AksenovD.A. GrishinI.Y. AksenovN.A. WangH. DuL. BetancourtT. PellyS.C. KornienkoA. RubinM. [3 + 2]-Annulation of pyridinium ylides with 1-chloro-2-nitrostyrenes unveils a tubulin polymerization inhibitor.Org. Biomol. Chem.202119337234724510.1039/D1OB01141C 34387294
     [Google Scholar]
  24. ChandrashekharappaS. VenugopalaK.N. VenugopalaR. PadmashaliB. Qualitative anti-tubercular activity of synthetic ethyl 7-acetyl2-substituted-3-(4-substituted benzoyl) indolizine-1-carboxylate analogues.J. Appl. Pharm. Sci.20199212412810.7324/JAPS.2019.90217
     [Google Scholar]
  25. VenugopalaK.N. TratratC. PillayM. MahomoodallyF.M. BhandaryS. ChopraD. MorsyM.A. HarounM. AldhubiabB.E. AttimaradM. NairA.B. SreeharshaN. VenugopalaR. ChandrashekharappaS. AlwassilO.I. OdhavB. Anti-tubercular activity of substituted 7-methyl and 7-formylindolizines and in silico study for prospective molecular target identification.Antibiotics (Basel)20198424710.3390/antibiotics8040247 31816928
     [Google Scholar]
  26. HazraA. MondalS. MaityA. NaskarS. SahaP. PairaR. SahuK.B. PairaP. GhoshS. SinhaC. SamantaA. BanerjeeS. MondalN.B. Amberlite–IRA-402 (OH) ion exchange resin mediated synthesis of indolizines, pyrrolo [1,2-a] quinolines and isoquinolines: Antibacterial and antifungal evaluation of the products.Eur. J. Med. Chem.20114662132214010.1016/j.ejmech.2011.02.066 21440339
     [Google Scholar]
  27. Faghih-MirzaeiE. SeifiM. AbaszadehM. ZomorodianK. HelaliH. Design, Synthesis, Biological Evaluation and Molecular Modeling Study of Novel Indolizine-1-Carbonitrile Derivatives as Potential Anti-Microbial Agents.Iran. J. Pharm. Res.2018173883895 30127812
     [Google Scholar]
  28. AttalahK.M. AbdallaA.N. AslamA. AhmedM. AbourehabM.A.S. ElSawyN.A. GoudaA.M. Ethyl benzoate bearing pyrrolizine/indolizine moieties: Design, synthesis and biological evaluation of anti-inflammatory and cytotoxic activities.Bioorg. Chem.20209410337110.1016/j.bioorg.2019.103371 31708230
     [Google Scholar]
  29. VenugopalaK.N. Al-AttraqchiO.H.A. TratratC. NayakS.K. MorsyM.A. AldhubiabB.E. AttimaradM. NairA.B. SreeharshaN. VenugopalaR. HarounM. GirishM.B. ChandrashekharappaS. AlwassilO.I. OdhavB. Novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates as promising anti-inflammatory agents: Molecular modeling studies.Biomolecules201991166110.3390/biom9110661 31661893
     [Google Scholar]
  30. BaussanneI. FirstovaO. DediuA.B. LarosaC. FurduiB. GhineaI.O. ThomasA. ChiericiS. DinicaR. DemeunynckM. Interest of novel N-alkylpyridinium-indolizine hybrids in the field of Alzheimer’s disease: Synthesis, characterization and evaluation of antioxidant activity, cholinesterase inhibition, and amyloid fibrillation interference.Bioorg. Chem.202111610539010.1016/j.bioorg.2021.105390 34670332
     [Google Scholar]
  31. TatipamulaV.B. KolliM.K. LaguS.B. PaidiK.R. P, R.R.; Yejella, R.P. Novel indolizine derivatives lowers blood glucose levels in streptozotocin-induced diabetic rats: A histopathological approach.Pharmacol. Rep.201971223324210.1016/j.pharep.2018.11.004 30807980
     [Google Scholar]
  32. BasavarajM. GilesD. DasA.K. JanadriS. AndhaleG.S. Design, synthesis and chemical stability of indolizine derivatives for antidiabetic activity. Nucleos.Nucleot. Nucleic Acids202241111127114010.1080/15257770.2022.2100418 35856484
     [Google Scholar]
  33. ChenS. XiaZ. NagaiM. LuR. KostikE. PrzewlokaT. SongM. ChimmanamadaD. JamesD. ZhangS. JiangJ. OnoM. KoyaK. SunL. Novel indolizine compounds as potent inhibitors of phosphodiesterase IV (PDE4): Structure–activity relationship.MedChemComm20112317618010.1039/C0MD00215A
     [Google Scholar]
  34. MoiseI.M. GhinetA. BeleiD. DuboisJ. FarceA. BîcuE. New indolizine–chalcones as potent inhibitors of human farnesyltransferase: Design, synthesis and biological evaluation.Bioorg. Med. Chem. Lett.201626153730373410.1016/j.bmcl.2016.05.074 27282741
     [Google Scholar]
  35. LucescuL. BicuE. BeleiD. DuboisJ. GhinetA. Synthesis and biological evaluation of some new indolizine derivatives as antitumoral agents.Lett. Drug Des. Discov.201613647948810.2174/1570180812666151022221628
     [Google Scholar]
  36. YuB. QiP.P. ShiX.J. HuangR. GuoH. ZhengY.C. YuD.Q. LiuH.M. Efficient synthesis of new antiproliferative steroidal hybrids using the molecular hybridization approach.Eur. J. Med. Chem.201611724125510.1016/j.ejmech.2016.04.024 27105028
     [Google Scholar]
  37. IvasivV. AlbertiniC. GonçalvesA.E. RossiM. BolognesiM.L. Molecular hybridization as a tool for designing multitarget drug candidates for complex diseases.Curr. Top. Med. Chem.201919191694171110.2174/1568026619666190619115735 31237210
     [Google Scholar]
  38. GontijoV.S. ViegasF.P.D. OrtizC.J.C. de Freitas SilvaM. DamasioC.M. RosaM.C. CamposT.G. CoutoD.S. Tranches DiasK.S. ViegasC. Molecular hybridization as a tool in the design of multi-target directed drug candidates for neurodegenerative diseases.Curr. Neuropharmacol.202018534840710.2174/1385272823666191021124443 31631821
     [Google Scholar]
  39. de Sena Murteira PinheiroP. FrancoL.S. MontagnoliT.L. FragaC.A.M. Molecular hybridization: A powerful tool for multitarget drug discovery.Expert Opin. Drug Discov.202419445147010.1080/17460441.2024.2322990 38456452
     [Google Scholar]
  40. AlkhzemA.H. WoodmanT.J. BlagbroughI.S. Design and synthesis of hybrid compounds as novel drugs and medicines.RSC Advances20221230194701948410.1039/D2RA03281C 35865575
     [Google Scholar]
  41. PossoM.C. DominguesF.C. FerreiraS. SilvestreS. Development of phenothiazine hybrids with potential medicinal interest: A review.Molecules202227127610.3390/molecules27010276 35011508
     [Google Scholar]
  42. AbdelSamadA.L. El-SaadiM.T. GoudaA.M. AboulMagd, A.M. Pyrrolizine/indolizine-bearing (un)substituted isoindole moiety: design, synthesis, antiproliferative and MDR reversal activities, and in silico studies.RSC Advances20231344307533077010.1039/D3RA05310E 37869384
     [Google Scholar]
  43. MoiseI.M. BîcuE. FarceA. DuboisJ. GhinetA. Indolizine-phenothiazine hybrids as the first dual inhibitors of tubulin polymerization and farnesyltransferase with synergistic antitumor activity.Bioorg. Chem.202010310418410.1016/j.bioorg.2020.104184 32891861
     [Google Scholar]
  44. ParkS. KimE.H. KimJ. KimS.H. KimI. Biological evaluation of indolizine-chalcone hybrids as new anticancer agents.Eur. J. Med. Chem.201814443544310.1016/j.ejmech.2017.12.056 29288944
     [Google Scholar]
  45. WanY. LiY. YanC. WenJ. TangZ. Discovery of novel indazole-acylsulfonamide hybrids as selective Mcl-1 inhibitors.Bioorg. Chem.202010410421710.1016/j.bioorg.2020.104217 32911192
     [Google Scholar]
  46. Pérez-VillanuevaJ. Matadamas-MartínezF. Yépez-MuliaL. Pérez-KoldenkovaV. Leyte-LugoM. Rodríguez-VillarK. Cortés-BenítezF. Macías-JiménezA.P. González-SánchezI. Romero-VelásquezA. Palacios-EspinosaJ.F. Soria-ArtecheO. synthesis and cytotoxic activity of combretastatin A-4 and 2,3-diphenyl-2H-indazole hybrids.Pharmaceuticals (Basel)202114881510.3390/ph14080815 34451912
     [Google Scholar]
  47. LiuJ. PengX. DaiY. ZhangW. RenS. AiJ. GengM. LiY. Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold.Org. Biomol. Chem.201513287643765410.1039/C5OB00778J 26080733
     [Google Scholar]
  48. AmanW. LeeJ. KimM. YangS. JungH. HahJ.M. Discovery of highly selective CRAF inhibitors, 3-carboxamido-2H-indazole-6-arylamide: In silico FBLD design, synthesis and evaluation.Bioorg. Med. Chem. Lett.20162641188119210.1016/j.bmcl.2016.01.037 26810260
     [Google Scholar]
  49. Ciurlă-LucescuL. BîcuE. BeleiD. GhinetA. New indazole-indolizine-triazine hybrid molecules with farnesyltransferase inhibitory activity.Results Chem.2024710145110.1016/j.rechem.2024.101451
     [Google Scholar]
  50. DumitriuG.M. GhinetA. BeleiD. RigoB. GautretP. DuboisJ. BicuE. Investigation of new phenothiazine and carbazole derivatives as potential inhibitors of human farnesyltransferase.Lett. Drug Des. Discov.2014122859210.2174/1570180811666140909010435
     [Google Scholar]
  51. ShoemakerR.H. The NCI60 human tumour cell line anticancer drug screen.Nat. Rev. Cancer200661081382310.1038/nrc1951 16990858
     [Google Scholar]
  52. SkehanP. StorengR. ScudieroD. MonksA. McMahonJ. VisticaD. WarrenJ.T. BokeschH. KenneyS. BoydM.R. New colorimetric cytotoxicity assay for anticancer-drug screening.J. Natl. Cancer Inst.199082131107111210.1093/jnci/82.13.1107 2359136
     [Google Scholar]
  53. BoydM.R. The NCI in vitro anticancer drug discovery screen. In: Anticancer Drug Development Guide. TeicherB.A. Totowa, NJHumana Press1997234210.1007/978‑1‑4615‑8152‑9_2
     [Google Scholar]
  54. SmithC.B. The C=O Bond, Part VI: Esters and the rule of three.Spectroscopy (Springf.)2018332023
     [Google Scholar]
  55. SmithC.B. Group wavenumbers and an introduction to the spectroscopy of benzene rings.Spectroscopy (Springf.)2016313437
     [Google Scholar]
  56. RenY. WangY. LiG. ZhangZ. MaL. ChengB. ChenJ. Discovery of novel benzimidazole and indazole analogues as tubulin polymerization inhibitors with potent anticancer activities.J. Med. Chem.20216484498451510.1021/acs.jmedchem.0c01837 33788562
     [Google Scholar]
  57. ZhuT. WangS.H. LiD. WangS.Y. LiuX. SongJ. WangY.T. ZhangS.Y. Progress of tubulin polymerization activity detection methods.Bioorg. Med. Chem. Lett.20213712769810.1016/j.bmcl.2020.127698 33468346
     [Google Scholar]
  58. EbenezerO. ShapiM. TuszynskiJ.A. A review of the recent developments of molecular hybrids targeting tubulin polymerization.Int. J. Mol. Sci.2022237400110.3390/ijms23074001 35409361
     [Google Scholar]
  59. GhinetA. AbuhaieC.M. GautretP. RigoB. DuboisJ. FarceA. BeleiD. BîcuE. Studies on indolizines. Evaluation of their biological properties as microtubule-interacting agents and as melanoma targeting compounds.Eur. J. Med. Chem.20158911512710.1016/j.ejmech.2014.10.041 25462232
     [Google Scholar]
/content/journals/lddd/10.2174/0115701808323543241018053705
Loading
Exploring the Antitumor Potential of New Indazole-indolizines Designed by Molecular Hybridization
Letters in Drug Design & Discovery 21, 4046 (2024); https://doi.org/10.2174/0115701808323543241018053705
/content/journals/lddd/10.2174/0115701808323543241018053705
/content/journals/lddd/10.2174/0115701808323543241018053705
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
Keyword(s): [3+2] cycloaddition; farnesyltransferase; hybrid molecule; in vitro anticancer activity; indazole; Indolizine; nitrogen-containing heterocycle

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