Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Medicinal Chemistry
  4. Volume 20, Issue 9
  5. Article
Volume 20, Issue 9
  • ISSN: 1573-4064
  • E-ISSN:

Abstract

Background

Vascular endothelial growth factor receptor-2 (VEGFR-2) is a critical protein involved in tumor progression, making it an attractive target for cancer therapy.

Objective

This study aimed to synthesize and evaluate novel thieno[2,3-]pyrimidine analogues as potential anticancer VEGFR-2 inhibitors.

Methods

The thieno[2,3-]pyrimidine analogues were synthesized following the pharmacophoric features of VEGFR-2 inhibitors. The anticancer potential was assessed against PC3 and HepG2 cell lines. The VEGFR-2 inhibition was evaluated through IC determination. Cell cycle analysis and apoptosis assays were performed to elucidate the mechanisms of action. Molecular docking, molecular dynamics simulations, MM-GBSA, and PLIP studies were conducted to investigate the binding affinities and interactions with VEGFR-2. Additionally, ADMET studies were performed.

Results

Compound demonstrated significant anti-proliferative activities with IC values of 16.35 µM and 8.24 µM against PC3 and HepG2 cell lines, respectively, surpassing sorafenib and exhibiting enhanced selectivity indices. Furthermore, compound showed an IC value of 73 nM for VEGFR-2 inhibition. Cell cycle analysis revealed G2-M phase arrest, while apoptosis assays demonstrated increased apoptosis in HepG2 cells. Molecular docking and dynamic simulations confirmed the binding affinity and interaction of compound with VEGFR-2, supported by MM-GBSA and PLIP studies. ADMET studies indicated the drug development potential of the synthesized thieno[2,3-]pyrimidines.

Conclusion

The study highlights compound as a promising VEGFR-2 inhibitor with potent anti-proliferative activities. Its mechanism of action involves cell cycle arrest and induction of apoptosis. Further, molecular docking and dynamic simulations support the strong binding affinity of compound to VEGFR-2.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/mc/10.2174/0115734064285433240513092047
2024-05-24
2024-11-14

  • From This Site

    /content/journals/mc/10.2174/0115734064285433240513092047
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. CuradoM.P. VotiL. Sortino-RachouA.M. Cancer registration data and quality indicators in low and middle income countries: Their interpretation and potential use for the improvement of cancer care.Cancer Causes Control200920575175610.1007/s10552‑008‑9288‑5 19112603
     [Google Scholar]
  2. CancerW.H.O. Fact sheet.,Available from: http://www.who.int/news-room/fact-sheets/detail/cancer
  3. GrantS.K. Therapeutic protein kinase inhibitors.Cell. Mol. Life Sci.20096671163117710.1007/s00018‑008‑8539‑7 19011754
     [Google Scholar]
  4. CohenP. CrossD. JänneP.A. Kinase drug discovery 20 years after imatinib: Progress and future directions.Nat. Rev. Drug Discov.202120755156910.1038/s41573‑021‑00195‑4 34002056
     [Google Scholar]
  5. WangX. BoveA.M. SimoneG. MaB. Molecular bases of VEGFR-2-mediated physiological function and pathological role.Front. Cell Dev. Biol.2020859928110.3389/fcell.2020.599281 33304904
     [Google Scholar]
  6. ShahA.A. KamalM.A. AkhtarS. Tumor angiogenesis and VEGFR-2: Mechanism, pathways and current biological therapeutic interventions.Curr. Drug Metab.2021221505910.2174/18755453MTEwxNzQ0x 33076807
     [Google Scholar]
  7. LiuX.J. ZhaoH.C. HouS.J. ZhangH.J. ChengL. YuanS. ZhangL.R. SongJ. ZhangS.Y. ChenS.W. Recent development of multi-target VEGFR-2 inhibitors for the cancer therapy.Bioorg. Chem.202313310642510.1016/j.bioorg.2023.106425 36801788
     [Google Scholar]
  8. GongT. LuoY. WangY. ZhengC. FangJ. MinL. ZhouY. TuC. Research, Multiple pulmonary metastases of recurrent Giant cell tumor of bone with expression of VEGFR-2 successfully controlled by Denosumab and Apatinib: a case report and literature review.Cancer Management202144474454
     [Google Scholar]
  9. ModiS.J. KulkarniV.M. Vascular endothelial growth factor receptor (VEGFR-2)/KDR inhibitors: Medicinal chemistry perspective.Med. Drug Discov.2019210000910.1016/j.medidd.2019.100009
     [Google Scholar]
  10. ChengK. LiuC-F. RaoG-W. Anti-angiogenic agents: A review on vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors.J. Curr. Med. Chem.202128132540256410.2174/1875533XMTA2ENjE9z 32407259
     [Google Scholar]
  11. FarghalyT.A. Al-HasaniW.A. AbdulwahabH.G. An updated patent review of VEGFR-2 inhibitors (2017-present).Expert Opin. Ther. Pat.20213111989100710.1080/13543776.2021.1935872 34043477
     [Google Scholar]
  12. HolmesK. RobertsO.L. ThomasA.M. CrossM.J. Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition.Cell. Signal.200719102003201210.1016/j.cellsig.2007.05.013 17658244
     [Google Scholar]
  13. MorabitoA. De MaioE. Di MaioM. NormannoN. PerroneF. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: Current status and future directions.Oncologist200611775376410.1634/theoncologist.11‑7‑753 16880234
     [Google Scholar]
  14. JamilM.O. HathawayA. MehtaA. Tivozanib: Status of development.Curr. Oncol. Rep.20151762410.1007/s11912‑015‑0451‑3 25895472
     [Google Scholar]
  15. Al-SalamaZ.T. SyedY.Y. ScottL.J. Lenvatinib: A review in hepatocellular carcinoma.Drugs201979666567410.1007/s40265‑019‑01116‑x 30993651
     [Google Scholar]
  16. EttrichT.J. SeufferleinT. Regorafenib.Small Molecules in Oncology20184556
     [Google Scholar]
  17. El-MetwallyS.A. Abou-El-RegalM.M. EissaI.H. MehanyA.B.M. MahdyH.A. ElkadyH. ElwanA. ElkaeedE.B. Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents.Bioorg. Chem.202111210494710.1016/j.bioorg.2021.104947 33964580
     [Google Scholar]
  18. El-AdlK. SakrH.M. YousefR.G. MehanyA.B.M. MetwalyA.M. ElhendawyM.A. RadwanM.M. ElSohlyM.A. AbulkhairH.S. EissaI.H. Discovery of new quinoxaline-2(1H)-one-based anticancer agents targeting VEGFR-2 as inhibitors: Design, synthesis, and anti-proliferative evaluation.Bioorg. Chem.202111410510510.1016/j.bioorg.2021.105105 34175720
     [Google Scholar]
  19. AlanaziM.M. MahdyH.A. AlsaifN.A. ObaidullahA.J. AlkahtaniH.M. Al-MehiziaA.A. AlsubaieS.M. DahabM.A. EissaI.H. New bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, in silico studies, and anticancer evaluation.Bioorg. Chem.202111210494910.1016/j.bioorg.2021.104949 34023640
     [Google Scholar]
  20. YousefR.G. SakrH.M. EissaI.H. MehanyA.B.M. MetwalyA.M. ElhendawyM.A. RadwanM.M. ElSohlyM.A. AbulkhairH.S. El-AdlK. New quinoxaline-2(1 H) -ones as potential VEGFR-2 inhibitors: Design, synthesis, molecular docking, ADMET profile and anti-proliferative evaluations.New J. Chem.20214536169491696410.1039/D1NJ02509K
     [Google Scholar]
  21. SobhE.A. DahabM.A. ElkaeedE.B. AlsfoukA.A. IbrahimI.M. MetwalyA.M. EissaI.H. Discovery of new thieno[2, 3-d]pyrimidines as EGFR tyrosine kinase inhibitors for cancer treatment.Future Med. Chem.2023151311671184
     [Google Scholar]
  22. SobhE.A. DahabM.A. ElkaeedE.B. AlsfoukA.A. IbrahimI.M. MetwalyA.M. EissaI.H. Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3- d]pyrimidine derivatives as new EGFR inhibitors.J. Enzyme Inhib. Med. Chem.2023381222057910.1080/14756366.2023.2220579 37288786
     [Google Scholar]
  23. SobhE.A. DahabM.A. ElkaeedE.B. AlsfoukB.A. IbrahimI.M. MetwalyA.M. EissaI.H. A novel thieno[2,3‐ d]pyrimidine derivative inhibiting vascular endothelial growth factor receptor‐2: A story of computer‐aided drug discovery.Drug Dev. Res.20238461247126510.1002/ddr.22083 37232504
     [Google Scholar]
  24. AbdelhaleemE.F. AbdelhameidM.K. KassabA.E. KandeelM.M. Design and synthesis of thienopyrimidine urea derivatives with potential cytotoxic and pro-apoptotic activity against breast cancer cell line MCF-7.Eur. J. Med. Chem.20181431807182510.1016/j.ejmech.2017.10.075 29133058
     [Google Scholar]
  25. ElkaeedE.B. YousefR.G. ElkadyH. GobaaraI.M.M. AlsfoukB.A. HuseinD.Z. IbrahimI.M. MetwalyA.M. EissaI.H. Design, synthesis, docking, DFT, MD simulation studies of a new nicotinamide-based derivative: In vitro anticancer and VEGFR-2 inhibitory effects.Molecules20222714460610.3390/molecules27144606 35889478
     [Google Scholar]
  26. EissaI.H. YousefR.G. ElkadyH. ElkaeedE.B. AlsfoukA.A. HuseinD.Z. IbrahimI.M. ElhendawyM.A. GodfreyM. MetwalyA.M. Design, semi-synthesis, anti-cancer assessment, docking, MD simulation, and DFT studies of novel theobromine-based derivatives as VEGFR-2 inhibitors and apoptosis inducers.Comput. Biol. Chem.202310710795310.1016/j.compbiolchem.2023.107953 37673011
     [Google Scholar]
  27. EissaI.H. YousefR.G. SamiM. ElkaeedE.B. AlsfoukB.A. IbrahimI.M. HuseinD.Z. ElkadyH. MetwalyA.M. Exploring the anticancer properties of a new nicotinamide analogue: Investigations into in silico analysis, antiproliferative effects, selectivity, VEGFR-2 inhibition, apoptosis induction, and migration suppression.Pathol. Res. Pract.202325215492410.1016/j.prp.2023.154924 37956639
     [Google Scholar]
  28. EissaI.H. YousefR.G. AsmaeyM.A. ElkadyH. HuseinD.Z. AlsfoukA.A. IbrahimI.M. ElkadyM.A. ElkaeedE.B. MetwalyA.M. Computer-assisted drug discovery (CADD) of an anti-cancer derivative of the theobromine alkaloid inhibiting VEGFR-2.Saudi Pharm. J.2023101852
     [Google Scholar]
  29. EissaI.H. YousefR.G. ElkadyH. ElkaeedE.B. AlsfoukB.A. HuseinD.Z. AsmaeyM.A. IbrahimI.M. MetwalyA.M. Anti-breast cancer potential of a new xanthine derivative: In silico, antiproliferative, selectivity, VEGFR-2 inhibition, apoptosis induction and migration inhibition studies.Pathol. Res. Pract.202325115489410.1016/j.prp.2023.154894 37857034
     [Google Scholar]
  30. DahabM.A. MahdyH.A. ElkadyH. TaghourM.S. ElwanA. ElkadyM.A. ElsakkaE.G.E. ElkaeedE.B. AlsfoukA.A. IbrahimI.M. MetwalyA.M. EissaI.H. Semi-synthesized anticancer theobromine derivatives targeting VEGFR-2: in silico and in vitro evaluations.J. Biomol. Struct. Dyn.20244284214423310.1080/07391102.2023.2219333 37261471
     [Google Scholar]
  31. EissaI.H. MohammadH. QassemO.A. YounisW. AbdelghanyT.M. ElshafeeyA. Abd Rabo MoustafaM.M. SeleemM.N. MayhoubA.S. Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus.Eur. J. Med. Chem.2017130738510.1016/j.ejmech.2017.02.044 28249208
     [Google Scholar]
  32. SobhE.A. DahabM.A. ElkaeedE.B. AlsfoukA.A. IbrahimI.M. MetwalyA.M. EissaI.H. Computer aided drug discovery (CADD) of a thieno[2,3-d]pyrimidine derivative as a new EGFR inhibitor targeting the ribose pocket.J. Biomol. Struct. Dyn.202442523692391 37129193
     [Google Scholar]
  33. GolubA.G. BdzholaV.G. BriukhovetskaN.V. BalandaA.O. KukharenkoO.P. KoteyI.M. OstrynskaO.V. YarmolukS.M. Synthesis and biological evaluation of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids as inhibitors of human protein kinase CK2.Eur. J. Med. Chem.201146387087610.1016/j.ejmech.2010.12.025 21276643
     [Google Scholar]
  34. AbbasS.E. Abdel GawadN.M. GeorgeR.F. AkarY.A. Synthesis, antitumor and antibacterial activities of some novel tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives.Eur. J. Med. Chem.20136519520410.1016/j.ejmech.2013.04.055 23708013
     [Google Scholar]
  35. OstrynskaO.V. BalandaA.O. BdzholaV.G. GolubA.G. KoteyI.M. KukharenkoO.P. GryshchenkoA.A. BriukhovetskaN.V. YarmolukS.M. Design and synthesis of novel protein kinase CK2 inhibitors on the base of 4-aminothieno[2,3-d]pyrimidines.Eur. J. Med. Chem.201611514816010.1016/j.ejmech.2016.03.004 27017545
     [Google Scholar]
  36. ElkadyH. ElwanA. El-MahdyH.A. DoghishA.S. IsmailA. TaghourM.S. ElkaeedE.B. EissaI.H. DahabM.A. MahdyH.A. KhalifaM.M. New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies.J. Enzyme Inhib. Med. Chem.202237140341610.1080/14756366.2021.2015343 34961427
     [Google Scholar]
  37. WangJ. LenardoM.J. Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies.J. Cell Sci.2000113575375710.1242/jcs.113.5.753 10671365
     [Google Scholar]
  38. LoK.K.W. LeeT.K.M. LauJ.S.Y. PoonW.L. ChengS.H. Luminescent biological probes derived from ruthenium(II) estradiol polypyridine complexes.Inorg. Chem.200847120020810.1021/ic701735q 18067284
     [Google Scholar]
  39. SabtA. AbdelhafezO.M. El-HaggarR.S. MadkourH.M.F. EldehnaW.M. El-KhrisyE.E.D.A.M. Abdel-RahmanM.A. RashedL.A. Novel coumarin-6-sulfonamides as apoptotic anti-proliferative agents: Synthesis, in vitro biological evaluation, and QSAR studies.J. Enzyme Inhib. Med. Chem.20183311095110710.1080/14756366.2018.1477137 29944015
     [Google Scholar]
  40. HagrasM. SalehM.A. Ezz EldinR.R. AbuelkhirA.A. KhidrE.G. El-HusseinyA.A. El-MahdyH.A. ElkaeedE.B. EissaI.H. 1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: Design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies.J. Enzyme Inhib. Med. Chem.202237138640210.1080/14756366.2021.2015342 34923885
     [Google Scholar]
  41. ElwanA. AbdallahA.E. MahdyH.A. DahabM.A. TaghourM.S. ElkaeedE.B. MehanyA.B.M. NabeehA. AdelM. AlsfoukA.A. ElkadyH. EissaI.H. Modified benzoxazole-based VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, and anti-proliferative evaluation.Molecules20222715504710.3390/molecules27155047 35956997
     [Google Scholar]
  42. ElkaeedE.B. YoussefF.S. EissaI.H. ElkadyH. AlsfoukA.A. AshourM.L. El HassabM.A. Abou-SeriS.M. MetwalyA.M. Multi-step in silico discovery of natural drugs against COVID-19 targeting main protease.Int. J. Mol. Sci.20222313691210.3390/ijms23136912 35805916
     [Google Scholar]
  43. YousefR.G. ElwanA. GobaaraI.M.M. MehanyA.B.M. EldehnaW.M. El-MetwallyS.A.A. A AlsfoukB. ElkaeedE.B. MetwalyA.M. EissaI.H. Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: In vitro and in silico studies.J. Enzyme Inhib. Med. Chem.20223712206222210.1080/14756366.2022.2110868 35980113
     [Google Scholar]
  44. TormyshevV. FlinnA. TrukhinD. RogozhnikovaO. MikhalinaT. TroitskayaT. Aryl alkyl ketones in a one-pot Gewald synthesis of 2-aminothiophenes.Synlett20062006162559256410.1055/s‑2006‑951484
     [Google Scholar]
  45. KandeelM.M. MounirA.A. RefaatH.M. KassabA.E. Synthesis of thieno[2, 3-d] pyrimidines, thieno[2, 3-d] triazinones and thieno[2, 3-e] diazepinones of anticipated anti-cancer activity.J. Chem. Res.201236210511010.3184/174751912X13282020691270
     [Google Scholar]
  46. SinghB.S. LoboH.R. PinjariD.V. JaragK.J. PanditA.B. ShankarlingG.S. Comparative material study and synthesis of 4-(4-nitrophenyl)oxazol-2-amine via sonochemical and thermal method.Ultrason. Sonochem.201320263363910.1016/j.ultsonch.2012.09.002 23062955
     [Google Scholar]
  47. MosmannT. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays.J. Immunol. Methods1983651-2556310.1016/0022‑1759(83)90303‑4 6606682
     [Google Scholar]
  48. DenizotF. LangR. Rapid colorimetric assay for cell growth and survival.J. Immunol. Methods198689227127710.1016/0022‑1759(86)90368‑6 3486233
     [Google Scholar]
  49. ThabrewM.I. HughesR.D. McFarlaneI.G. Screening of hepatoprotective plant components using a HepG2 cell cytotoxicity assay.J. Pharm. Pharmacol.201149111132113510.1111/j.2042‑7158.1997.tb06055.x 9401951
     [Google Scholar]
  50. LiM. JiangD. BarnhartT.E. CaoT. EngleJ.W. ChenW. CaiW. Immuno-PET imaging of VEGFR-2 expression in prostate cancer with 89Zr-labeled ramucirumab.Am. J. Cancer Res.20199920372046 31598404
     [Google Scholar]
  51. ChuJ.S. GeF.J. ZhangB. WangY. SilvestrisN. LiuL.J. ZhaoC.H. LinL. BrunettiA.E. FuY.L. WangJ. ParadisoA. XuJ.M. Expression and prognostic value of VEGFR-2, PDGFR-β, and c-Met in advanced hepatocellular carcinoma.J. Exp. Clin. Cancer Res.20133211610.1186/1756‑9966‑32‑16 23552472
     [Google Scholar]
  52. LiuY. GrayN.S. Rational design of inhibitors that bind to inactive kinase conformations.Nat. Chem. Biol.20062735836410.1038/nchembio799 16783341
     [Google Scholar]
  53. DietrichJ. HulmeC. HurleyL.H. The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: A structural analysis of the binding interactions of Gleevec®, Nexavar®, and BIRB-796.Bioorg. Med. Chem.201018155738574810.1016/j.bmc.2010.05.063 20621496
     [Google Scholar]
  54. FerreiraL.L.G. AndricopuloA.D. ADMET modeling approaches in drug discovery.Drug Discov. Today20192451157116510.1016/j.drudis.2019.03.015 30890362
     [Google Scholar]
  55. DeardenJ.C. In silico prediction of drug toxicity.J. Comput. Aided Mol. Des.2003172/411912710.1023/A:1025361621494 13677480
     [Google Scholar]
  56. IdakwoG. LuttrellJ. ChenM. HongH. ZhouZ. GongP. ZhangC. A review on machine learning methods for in silico toxicity prediction.J. Environ. Sci. Health Part C Environ. Carcinog. Ecotoxicol. Rev.201836416919110.1080/10590501.2018.1537118 30628866
     [Google Scholar]
  57. KruhlakN.L. BenzR.D. ZhouH. ColatskyT.J. (Q)SAR modeling and safety assessment in regulatory review.Clin. Pharmacol. Ther.201291352953410.1038/clpt.2011.300 22258468
     [Google Scholar]
/content/journals/mc/10.2174/0115734064285433240513092047
Loading
New Thieno[2,3-d]pyrimidines as Anticancer VEGFR-2 Inhibitors with Apoptosis Induction: Design, Synthesis, and Biological and In Silico Studies
Medicinal Chemistry 20, 876 (2024); https://doi.org/10.2174/0115734064285433240513092047
/content/journals/mc/10.2174/0115734064285433240513092047
/content/journals/mc/10.2174/0115734064285433240513092047
Loading

Data & Media loading...

Supplements

file format download Download

  • Article Type:     Research Article
Keyword(s): Anticancer; apoptosis; MD simulations; molecular docking; thieno[2,3-d]pyrimidine; VEGFR-2 inhibitors

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