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2000
Volume 21, Issue 7
  • ISSN: 1573-4064
  • E-ISSN: 1875-6638

Abstract

Background

In many types of cancer, uncontrolled growth and proliferation of cells occur due to abnormalities in their genes, mutations of pro-apoptotic proteins, or upregulation of anti-apoptotic proteins. Triazolinedione and pyrrole derivatives are compounds with anti-microbial, anti-fungal, anti-inflammatory, and anti-cancer activities. Pyrrole and its derivatives are critical heterocycle compounds that are significant in anticancer studies and highly preferred in research.

Objective

This study aimed to investigate the effects of dihydropyrrole derivatives substituted with triazolinedione on the MCF-7 (breast cancer) cell line’s apoptosis, ER stress, and heat shock genes.

Methods

The mRNA levels of apoptosis, ER stress, and heat shock proteins were assessed by qRT-PCR method in the MCF-7 cell line. The investigation of ADMET features, crucial pharmacokinetic indices for the potential candidacy of compounds as drugs, has been meticulously designed. -induced molecular docking studies were conducted to further explore the interaction and elucidate the orientation of hybrid compounds within the active sites of BCL-2, PARP, HSP70, HSP90, and GRP78.

Results

It was determined that the compounds caused cell death by modulating apoptotic (compound ), ER stress, and heat shock proteins (compounds and ) through up- and down-regulation. Our findings have pointed to the effects of triazolinedione-substituted dihydropyrrole derivatives, exhibiting antitumor activity on apoptosis, ER stress, and heat shock genes in the MCF-7 cell line.

Conclusion

The compounds investigated in this study have been found to be promising for anticancer research.

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References

  1. FerlayJ. ColombetM. SoerjomataramI. ParkinD.M. PiñerosM. ZnaorA. BrayF. Cancer statistics for the year 2020: An overview.Int. J. Cancer2021149477878910.1002/ijc.33588 33818764
     [Google Scholar]
  2. BrayF. FerlayJ. SoerjomataramI. SiegelR.L. TorreL.A. JemalA. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.201868639442410.3322/caac.21492 30207593
     [Google Scholar]
  3. SanninoS. BrodskyJ.L. Targeting protein quality control pathways in breast cancer.BMC Biol.201715110910.1186/s12915‑017‑0449‑4 29145850
     [Google Scholar]
  4. MiuraM. Active participation of cell death in development and organismal homeostasis.Dev. Growth Differ.201153212513610.1111/j.1440‑169X.2010.01228.x 21338339
     [Google Scholar]
  5. HassanM. WatariH. AbuAlmaatyA. OhbaY. SakuragiN. Apoptosis and molecular targeting therapy in cancer.BioMed Res. Int.2014201412310.1155/2014/150845 25013758
     [Google Scholar]
  6. StrasserA. The roles of programmed cell death in tumor development and cancer therapy.Medicographia201436311318
     [Google Scholar]
  7. ŻołnowskaB. SławińskiJ. BrzozowskiZ. KawiakA. BelkaM. ZielińskaJ. BączekT. ChojnackiJ. Synthesis, molecular structure, anticancer activity, and QSAR study of N-(aryl/heteroaryl)-4-(1H-pyrrol-1-yl)benzenesulfonamide derivatives.Int. J. Mol. Sci.2018195148210.3390/ijms19051482 29772699
     [Google Scholar]
  8. MaesM.E. SchlampC.L. NickellsR.W. Live-cell imaging to measure BAX recruitment kinetics to mitochondria during apoptosis.PLoS One2017129e018443410.1371/journal.pone.0184434 28880942
     [Google Scholar]
  9. CampbellK.J. TaitS.W.G. Targeting BCL-2 regulated apoptosis in cancer.Open Biol.20188518000210.1098/rsob.180002 29769323
     [Google Scholar]
  10. OpfermanJ.T. KothariA. Anti-apoptotic BCL-2 family members in development.Cell Death Differ.2018251374510.1038/cdd.2017.170 29099482
     [Google Scholar]
  11. MalumbresM. BarbacidM. To cycle or not to cycle: A critical decision in cancer.Nat. Rev. Cancer20011322223110.1038/35106065 11902577
     [Google Scholar]
  12. McIlwainD.R. BergerT. MakT.W. Caspase functions in cell death and disease.Cold Spring Harb. Perspect. Biol.201354a00865610.1101/cshperspect.a008656 23545416
     [Google Scholar]
  13. LiuP.F. HuY.C. KangB.H. TsengY.K. WuP.C. LiangC.C. HouY.Y. FuT.Y. LiouH.H. HsiehI.C. GerL.P. ShuC.W. Expression levels of cleaved caspase-3 and caspase-3 in tumorigenesis and prognosis of oral tongue squamous cell carcinoma.PLoS One2017127e018062010.1371/journal.pone.0180620 28700659
     [Google Scholar]
  14. FaraoniI. GrazianiG. Role of BRCA mutations in cancer treatment with poly(ADP-ribose) polymerase (PARP) inhibitors.Cancers (Basel)2018101248710.3390/cancers10120487 30518089
     [Google Scholar]
  15. NiM. LeeA.S. ER chaperones in mammalian development and human diseases.FEBS Lett.2007581193641365110.1016/j.febslet.2007.04.045 17481612
     [Google Scholar]
  16. ReddyR.K. MaoC. BaumeisterP. AustinR.C. KaufmanR.J. LeeA.S. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: Role of ATP binding site in suppression of caspase-7 activation.J. Biol. Chem.200327823209152092410.1074/jbc.M212328200 12665508
     [Google Scholar]
  17. RichterK. HaslbeckM. BuchnerJ. The heat shock response: Life on the verge of death.Mol. Cell201040225326610.1016/j.molcel.2010.10.006 20965420
     [Google Scholar]
  18. ChatterjeeS. BurnsT. Targeting heat shock proteins in cancer: A promising therapeutic approach.Int. J. Mol. Sci.2017189197810.3390/ijms18091978 28914774
     [Google Scholar]
  19. ShaikhA.R. FarooquiM. SatputeR.H. AbedS. Overview on Nitrogen containing compounds and their assessment based on ‘International Regulatory Standards’.J. Drug Deliv. Ther.201886-s42442810.22270/jddt.v8i6‑s.2156
     [Google Scholar]
  20. FuldaS. Targeting apoptosis for anticancer therapy.Semin. Cancer Biol.201531848810.1016/j.semcancer.2014.05.002 24859747
     [Google Scholar]
  21. BhardwajV. GumberD. AbbotV. DhimanS. SharmaP. Pyrrole: A resourceful small molecule in key medicinal hetero-aromatics.RSC Advances2015520152331526610.1039/C4RA15710A
     [Google Scholar]
  22. FanH. PengJ. HamannM.T. HuJ.F. Corrigendum to “lamellarins and related pyrrole-derived alkaloids from marine organisms”.Chem. Rev.201011063850385010.1021/cr900322f
     [Google Scholar]
  23. GholapS.S. Pyrrole: An emerging scaffold for construction of valuable therapeutic agents.Eur. J. Med. Chem.2016110133110.1016/j.ejmech.2015.12.017 26807541
     [Google Scholar]
  24. ZhuT. ShenS. LuQ. YeX. DingW. ChenR. XieJ. ZhuW. XuJ. JiaL. WuW. MaT. Design and synthesis of novel N(4)-substituted thiosemicarbazones bearing a pyrrole unit as potential anticancer agents.Oncol. Lett.20171364493450010.3892/ol.2017.5995 28599449
     [Google Scholar]
  25. De BruyckerK. BillietS. HouckH.A. ChattopadhyayS. WinneJ.M. Du PrezF.E. Triazolinediones as highly enabling synthetic tools.Chem. Rev.201611663919397410.1021/acs.chemrev.5b00599 26900710
     [Google Scholar]
  26. PatelN.B. KhanI.H. RajaniS.D. Pharmacological evaluation and characterizations of newly synthesized 1,2,4-triazoles.Eur. J. Med. Chem.20104594293429910.1016/j.ejmech.2010.06.031 20630629
     [Google Scholar]
  27. CoriglianoD.M. SyedR. MessineoS. LupiaA. PatelR. ReddyC.V.R. DubeyP.K. ColicaC. AmatoR. De SarroG. AlcaroS. IndrasenaA. BrunettiA. Indole and 2,4-Thiazolidinedione conjugates as potential anticancer modulators.PeerJ20186e538610.7717/peerj.5386 30123711
     [Google Scholar]
  28. AtmacaH. IlhanS. KorkmazE. ZoraM. Endoplasmic reticulum stress‐induced apoptotic effects of novel 1-pyrroline (3,4‐dihydro‐2 H ‐pyrrole) derivatives on breast cancer cells.Chem. Biodivers.2022197e20220012310.1002/cbdv.202200123 35785434
     [Google Scholar]
  29. PuriS. PatilN.S. JuvaleK. Investigation of some diethyl (4-(dimethylamino)-2,5-dihydro-2,5-dioxo-1-phenyl-1H-pyrrol-3-yl)(hydroxy)methylphosphonate derivatives for In silico pharmacokinetic profile and In vitro anticancer activity.Chem. Zvesti202276116713672110.1007/s11696‑022‑02329‑3
     [Google Scholar]
  30. NanjanM. SankarM. RameshR. Synthesis and structure of nickel(II) complexes comprising pyrrole benzhydrazone ligands: In vitro Cytotoxicity and Apoptosis Studies.SSRN202310.2139/ssrn.4511208
     [Google Scholar]
  31. GarberováM. PotočňákI. TvrdoňováM. MajirskáM. Bago-PilátováM. BekešováS. KováčA. TakáčP. KhiratkarK. KudličkováZ. ElečkoJ. VilkováM. Derivatives incorporating acridine, pyrrole, and thiazolidine rings as promising antitumor agents.Molecules202328186616661610.3390/molecules28186616 37764394
     [Google Scholar]
  32. IngleJ. TirkeyA. PandeyS. BasuS. Small-molecule endoplasmic reticulum stress inducer triggers apoptosis in cancer cells.ChemMedChem20231824e20230043310.1002/cmdc.202300433 37964696
     [Google Scholar]
  33. AyarA. AksahinM. MesciS. YazganB. GülM. YıldırımT. Antioxidant, cytotoxic activity and pharmacokinetic studies by swiss adme, molinspiration, osiris and dft of phtad-substituted dihydropyrrole derivatives.Curr. Computeraided Drug Des.2022181526310.2174/1573409917666210223105722 33622227
     [Google Scholar]
  34. YazganB. Mesci̇S. AkşahinM. AyarA. GülM. YildirimT. PhTAD-substituted dihydropyrrole compounds regulate apoptotic cell death in MCF-7 cells.Erzincan Üniversitesi Fen Bilimleri Enstitüsü Dergisi202114273775010.18185/erzifbed.894125
     [Google Scholar]
  35. YazganB. Mesci̇S. AkşahinM. AyarA. GülM. YildirimT. ATP‐binding cassette transporters mediated chemoresistance in MCF-7 cells: Modulation by PhTAD-substituted dihydropyrrole compounds.Ahi. Evran. Med. J.202161778510.46332/aemj.896830
     [Google Scholar]
  36. MaloneyA. WorkmanP. HSP90 as a new therapeutic target for cancer therapy: The story unfolds.Expert Opin. Biol. Ther.20022132410.1517/14712598.2.1.3 11772336
     [Google Scholar]
  37. WellsJ.A. McClendonC.L. Reaching for high-hanging fruit in drug discovery at protein–protein interfaces.Nature200745071721001100910.1038/nature06526 18075579
     [Google Scholar]
  38. DongD. NiM. LiJ. XiongS. YeW. VirreyJ.J. MaoC. YeR. WangM. PenL. DubeauL. GroshenS. HofmanF.M. LeeA.S. Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development.Cancer Res.200868249850510.1158/0008‑5472.CAN‑07‑2950 18199545
     [Google Scholar]
  39. GulM. ElemesY. PelitE. DernektsiE. GeorgiouD. OikonomouK. LisT. SzafertS. Synthesis of PhTAD-substituted dihydropyrrole derivatives via stereospecific C–H amination.Res. Chem. Intermed.20174321031104510.1007/s11164‑016‑2681‑x
     [Google Scholar]
  40. MorrisG.M. HueyR. LindstromW. SannerM.F. BelewR.K. GoodsellD.S. OlsonA.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.J. Comput. Chem.200930162785279110.1002/jcc.21256 19399780
     [Google Scholar]
  41. RyanK. BolaňosB. SmithM. PaldeP.B. CuencaP.D. VanArsdaleT.L. NiessenS. ZhangL. BehennaD. OrnelasM.A. TranK.T. KaiserS. LumL. StewartA. GajiwalaK.S. Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1.J. Biol. Chem.202129610025110.1074/jbc.RA120.016573 33361107
     [Google Scholar]
  42. SchlechtR. ScholzS.R. DahmenH. WegenerA. SirrenbergC. MusilD. BomkeJ. EggenweilerH.M. MayerM.P. BukauB. Functional analysis of Hsp70 inhibitors.PLoS One2013811e7844310.1371/journal.pone.0078443 24265689
     [Google Scholar]
  43. LeeJ.H. ShinS.C. SeoS.H. SeoY.H. JeongN. KimC.W. KimE.E. KeumG. Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3- d]pyrimidines as potent Hsp90 inhibitors.Bioorg. Med. Chem. Lett.201727223724110.1016/j.bmcl.2016.11.062 27914802
     [Google Scholar]
  44. MurrayJ.B. DavidsonJ. ChenI. DavisB. DokurnoP. GrahamC.J. HarrisR. JordanA. MatassovaN. PedderC. RayS. RoughleyS.D. SmithJ. WalmsleyC. WangY. WhiteheadN. WilliamsonD.S. CasaraP. Le DiguarherT. HickmanJ. StarkJ. KotschyA. GenesteO. HubbardR.E. Establishing drug discovery and identification of hit series for the anti-apoptotic proteins, Bcl-2 and Mcl-1.ACS Omega2019458892890610.1021/acsomega.9b00611 31459977
     [Google Scholar]
  45. MaciasA.T. WilliamsonD.S. AllenN. BorgognoniJ. ClayA. DanielsZ. DokurnoP. DrysdaleM.J. FrancisG.L. GrahamC.J. HowesR. MatassovaN. MurrayJ.B. ParsonsR. ShawT. SurgenorA.E. TerryL. WangY. WoodM. MasseyA.J. Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: Insights into isoform selectivity.J. Med. Chem.201154124034404110.1021/jm101625x 21526763
     [Google Scholar]
  46. StebbinsC.E. RussoA.A. SchneiderC. RosenN. HartlF.U. PavletichN.P. Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent.Cell199789223925010.1016/S0092‑8674(00)80203‑2 9108479
     [Google Scholar]
  47. Schrödinger Protein preparation Wizard.2017Available from: https://www.schrodinger.com/life-science/learn/white-papers/protein-preparation-wizard/
    [Google Scholar]
  48. DenningtonR. KeithT. MillamJ. Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent.Open J. Biophys.2019726471
     [Google Scholar]
  49. The Scripps Research Institute. Stefano Forte.2010Available From: http://mgltools.scripps.edu.tr
  50. OyesakinY.M. Molecular docking and in-silico adme prediction of substituted (e)-4-styryl-7,8-dihydroquinazolin-5(6h)-ones and 5-((e)-styryl)pyrimidine[4,5-d]pyrimidine-2,4(1h,3h)-diones as potential sert inhibitors and antidepressants.American J. Pharmacol. Sci.2018612532
     [Google Scholar]
  51. PatelA. GandhiK. ShahS. PatelD. ChhatbarS. ShahD. PatelS. PatelH. BambharoliyaT. In silico study and solvent-free one-pot synthesis of tetrahydropyrimidine derivatives by mechanochemistry approach for targeting human neutrophil elastase against lung cancer.Curr. Computeraided Drug Des.202218429330610.2174/1573409918666220622232501 35747983
     [Google Scholar]
  52. LivakK.J. SchmittgenT.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)).Method. Methods200125440240810.1006/meth.2001.1262 11846609
     [Google Scholar]
  53. MehtaM. PatelS. PatelA. PatelY. ShahD. RathodK. ShahU. PatelM. BambharoliyaT. Molecular docking, in silico admet study and synthesis of quinoline derivatives as Dihydrofolate Reductase (DHFR) inhibitors: A solvent-free one-pot green approach through sonochemistry.Lett. Drug Des. Discov.202421350451910.2174/1570180820666221107090046
     [Google Scholar]
  54. VermaS. PathaniaA.S. BaranwalS. KumarP. Synthesis and in silico studies of quinazolinone derivatives as PARP-1 inhibitors.Lett. Drug Des. Discov.202017121552156510.2174/1570180817999200719152959
     [Google Scholar]
  55. ZhangJ. GaoY. ZhangZ. ZhaoJ. JiaW. XiaC. WangF. LiuT. Multi-therapies based on PARP inhibition: Potential therapeutic approaches for cancer treatment.J. Med. Chem.20226524160991612710.1021/acs.jmedchem.2c01352 36512711
     [Google Scholar]
  56. ElshemeyW.M. ElfikyA.A. IbrahimI.M. ElgoharyA.M. Interference of Chaga mushroom terpenoids with the attachment of SARS-CoV-2; in silico perspective.Comput. Biol. Med.202214510547810547810.1016/j.compbiomed.2022.105478 35421790
     [Google Scholar]
  57. AbbasiM. KhodarahmiG. AlimardanZ. KashfiK. HasanzadehF. MahmudA. Identification of new small molecules as dual FoxM1 and Hsp70 inhibitors using computational methods.Res. Pharm. Sci.202217663565610.4103/1735‑5362.359431 36704430
     [Google Scholar]
  58. WongF. OmoriS. DonghiaN.M. ZhengE.J. CollinsJ.J. Discovering small-molecule senolytics with deep neural networks.Nat. Aging20233673475010.1038/s43587‑023‑00415‑z
     [Google Scholar]
  59. LiuS. LiuX. JiangS. FuM. HuJ. LiuJ. FanX. FengY. ZhangS. WangJ. Protective mechanism of Paeoniae Radix Alba against chemical liver injury based on network pharmacology, molecular docking, and in vitro experiments.J. Tradit. Chin. Med. Sci.2024111556610.1016/j.jtcms.2023.12.005
     [Google Scholar]
  60. KidwaiM. VenktaramananR. MohanR. SapraP. Cancer chemotherapy and heterocyclic compounds.Curr. Med. Chem.20029121209122810.2174/0929867023370059 12052173
     [Google Scholar]
  61. ShiF. TaoZ.L. YuJ. TuS.J. Highly enantioselective synthesis of biologically important 2,5-dihydropyrroles via phosphoric acid-catalyzed three-component reactions and evaluation of their cytotoxicity.Tetrahedron Asymmetry201122232056206410.1016/j.tetasy.2011.11.020
     [Google Scholar]
  62. ZhouC.H. WangY. Recent researches in triazole compounds as medicinal drugs.Curr. Med. Chem.201219223928010.2174/092986712803414213 22320301
     [Google Scholar]
  63. BavadiM. NiknamK. ShahrakiO. Novel pyrrole derivatives bearing sulfonamide groups: Synthesis in vitro cytotoxicity evaluation, molecular docking and DFT study.J. Mol. Struct.2017114624225310.1016/j.molstruc.2017.06.003
     [Google Scholar]
  64. HiremathS.B. DevendrappaS.L. Safety and efficacy of tirapazamine as anti-cancer drug: A meta-analysis of randomized controlled trials.Int. J. Basic Clin. Pharmacol.20187478378310.18203/2319‑2003.ijbcp20181187
     [Google Scholar]
  65. ChohanZ.H. SumrraS.H. YoussoufiM.H. HaddaT.B. Metal based biologically active compounds: Design, synthesis, and antibacterial/antifungal/cytotoxic properties of triazole-derived Schiff bases and their oxovanadium(IV) complexes.Eur. J. Med. Chem.20104572739274710.1016/j.ejmech.2010.02.053 20338672
     [Google Scholar]
  66. RamR. RaniV. AbbotV. KapoorY. KonarD. KumarK. Recent synthetic and medicinal perspectives of pyrroles: An overview.J. Pharm. Chem. Sci.2017111732
     [Google Scholar]
  67. ZhanX. QinW. WangS. ZhaoK. XinY. WangY. QiQ. MaoZ. Synthesis and anti-cancer activity of 3-substituted benzoyl-4-substituted phenyl-1H-pyrrole derivatives.Anticancer. Agents Med. Chem.201717682183110.2174/1871520616666160923092718 27671311
     [Google Scholar]
  68. KaurM. SinghP. Targeting tyrosine kinase: Development of acridone – pyrrole – oxindole hybrids against human breast cancer.Bioorg. Med. Chem. Lett.2019291323510.1016/j.bmcl.2018.11.021 30446310
     [Google Scholar]
  69. MooreR.G. LangeT.S. RobinsonK. KimK.K. UzunA. HoranT.C. KawarN. YanoN. ChuS.R. MaoQ. BrardL. DePaepeM.E. PadburyJ.F. ArnoldL.A. BrodskyA. ShenT.L. SinghR.K. Efficacy of a non-hypercalcemic vitamin-D2 derived anti-cancer agent (MT19c) and inhibition of fatty acid synthesis in an ovarian cancer xenograft model.PLoS One201274e34443e3444310.1371/journal.pone.0034443 22509304
     [Google Scholar]
  70. FreyM.L. SimonJ. BrücknerM. MailänderV. MorsbachS. LandfesterK. Bio-orthogonal triazolinedione (TAD) crosslinked protein nanocapsules affect protein adsorption and cell interaction.Polym. Chem.202011233821383010.1039/D0PY00087F
     [Google Scholar]
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Examination of Triazolinedione-Derived Dihydropyrrole Hybrid Compounds: ER Stress-Related Apoptosis in Breast Cancer Cells, Molecular Docking, and ADMET Analysis
Med. Chem. 21, 707 (2025); https://doi.org/10.2174/0115734064328727240911112815
/content/journals/mc/10.2174/0115734064328727240911112815
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  • Article Type:     Research Article
Keyword(s): apoptosis; Breast cancer; dihydropyrrole; ER stress; HSP; molecular docking; triazolinedione

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