Skip to content
2000
Volume 32, Issue 24
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Background and Objective

Breast cancer is the most common form of cancer in women and is the leading cause of cancer-related deaths among women globally. In this study, we aimed to synthesize a series of tropane derivatives to investigate their Hsp90 inhibitory activity as well as their cytotoxic impact on breast cancer cells (MCF-7 and MDA-MB-231).

Methods

Novel fused-tropane derivatives were created and produced as inhibitors of Hsp90, taking inspiration from XL888, a tropane medication used for treating cancer. The target compounds were screened to determine their ability to inhibit the activity of Hsp90.

Results

All tropane derivatives displayed a good submicromolar inhibition of Hsp90 with IC values ranging from 52.64 to 76.05 nM, relative to XL888 reference medication (IC = 27.78 nM). Among all the compounds examined, tropane derivative exhibited the highest level of Hsp90 inhibitory action, with an IC value of 52.64 nM. Furthermore, the cytotoxic activity of all compounds was evaluated against two breast cancer cell lines, namely MCF-7 and MDA-MB-231. Tropane derivative exhibited greater potency than doxorubicin against both cell lines. In addition, it demonstrated a safety profile significantly superior to that of doxorubicin when tested on normal human cells (WI-38 cells), thereby confirming its exceptional level of safety. The western blotting analysis demonstrated a 2.4-fold reduction in Hsp90 expression in MCF-7 cells. Furthermore, the molecular docking analysis has provided additional evidence for the capacity of compound to effectively bind with the target Hsp90 enzyme.

Conclusion

We have succeeded in synthesizing novel tropane hybrids exhibiting significant anti-Hsp90 action, similar to XL888 analogues.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673313163240829094557
2024-09-13
2025-10-22

  • From This Site

    /content/journals/cmc/10.2174/0109298673313163240829094557
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. TranB. BedardP.L. Luminal-B breast cancer and novel therapeutic targets.Breast Cancer Res.201113622110.1186/bcr290422217398
     [Google Scholar]
  2. PerouC.M. SørlieT. EisenM.B. van de RijnM. JeffreyS.S. ReesC.A. PollackJ.R. RossD.T. JohnsenH. AkslenL.A. FlugeØ. PergamenschikovA. WilliamsC. ZhuS.X. LønningP.E. Børresen-DaleA.L. BrownP.O. BotsteinD. Molecular portraits of human breast tumours.Nature2000406679774775210.1038/3502109310963602
     [Google Scholar]
  3. De Mattos-ArrudaL. CortesJ. Breast cancer and HSP90 inhibitors: Is there a role beyond the HER2-positive subtype?Breast201221460460710.1016/j.breast.2012.04.00222560618
     [Google Scholar]
  4. ZagouriF. SergentanisT.N. ChrysikosD. PapadimitriouC.A. DimopoulosM.A. PsaltopoulouT. Hsp90 inhibitors in breast cancer: A systematic review.Breast201322556957810.1016/j.breast.2013.06.00323870456
     [Google Scholar]
  5. FriedlandJ.C. SmithD.L. SangJ. AcquavivaJ. HeS. ZhangC. ProiaD.A. Targeted inhibition of Hsp90 by ganetespib is effective across a broad spectrum of breast cancer subtypes.Invest. New Drugs2014321142410.1007/s10637‑013‑9971‑623686707
     [Google Scholar]
  6. SanchezJ. CarterT.R. CohenM.S. BlaggB.S.J. Old and new approaches to target the Hsp90 chaperone.Curr. Cancer Drug Targets202020425327010.2174/156800961966619120210133031793427
     [Google Scholar]
  7. LiZ.N. LuoY. HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review).Oncol. Rep.2022491610.3892/or.2022.844336367182
     [Google Scholar]
  8. TrepelJ. MollapourM. GiacconeG. NeckersL. Targeting the dynamic HSP90 complex in cancer.Nat. Rev. Cancer201010853754910.1038/nrc288720651736
     [Google Scholar]
  9. ZhangJ. LiH. LiuY. ZhaoK. WeiS. SugarmanE.T. LiuL. ZhangG. Targeting Hsp90 as a novel therapy for cancer: Mechanistic insights and translational relevance.Cells20221118277810.3390/cells1118277836139353
     [Google Scholar]
  10. MiyataY. Hsp90 inhibitor geldanamycin and its derivatives as novel cancer chemotherapeutic agents.Curr. Pharm. Des.20051191131113810.2174/138161205350758515853661
     [Google Scholar]
  11. BusseniusJ. BlazeyC.M. AayN. AnandN.K. ArcalasA. BaikT. BowlesO.J. BuhrC.A. CostanzoS. CurtisJ.K. DeFinaS.C. DubenkoL. HeuerT.S. HuangP. JaegerC. JoshiA. KennedyA.R. KimA.I. LaraK. LeeJ. LiJ. LougheedJ.C. MaS. MalekS. ManaloJ.C.L. MartiniJ.F. McGrathG. NicollM. NussJ.M. PackM. PetoC.J. TsangT.H. WangL. WombleS.W. YakesM. ZhangW. RiceK.D. Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90.Bioorg. Med. Chem. Lett.201222175396540410.1016/j.bmcl.2012.07.05222877636
     [Google Scholar]
  12. PiechowskaK. ŚwitalskaM. CytarskaJ. JarochK. ŁuczykowskiK. ChałupkaJ. WietrzykJ. MisiuraK. BojkoB. KruszewskiS. ŁączkowskiK.Z. Discovery of tropinone-thiazole derivatives as potent caspase 3/7 activators, and noncompetitive tyrosinase inhibitors with high antiproliferative activity: Rational design, one-pot tricomponent synthesis, and lipophilicity determination.Eur. J. Med. Chem.201917516217110.1016/j.ejmech.2019.05.00631082763
     [Google Scholar]
  13. IsmailN.S.M. GeorgeR.F. SeryaR.A.T. BaseliousF.N. El-ManawatyM. ShalabyE.M. GirgisA.S. Rational design, synthesis and 2D-QSAR studies of antiproliferative tropane-based compounds.RSC Advances2016610410191110192310.1039/C6RA21486J
     [Google Scholar]
  14. PetrouA. FesatidouM. GeronikakiA. Thiazole ring-A biologically active scaffold.Molecules20212611316610.3390/molecules2611316634070661
     [Google Scholar]
  15. ZarenezhadE. FarjamM. IrajiA. Synthesis and biological activity of pyrimidines-containing hybrids: Focusing on pharmacological application.J. Mol. Struct.2021123012983310.1016/j.molstruc.2020.129833
     [Google Scholar]
  16. MatinM.M. MatinP. RahmanM.R. Ben HaddaT. AlmalkiF.A. MahmudS. GhoneimM.M. AlruwailyM. AlshehriS. R.; Ben Hadda, T.; Almalki, F. A.; Mahmud, S.; Ghoneim, M. M.; Alruwaily M.; Alshehri, S.; Triazoles and their derivatives: Chemistry, synthesis, and therapeutic applications.Front. Mol. Biosci.2022986428610.3389/fmolb.2022.86428635547394
     [Google Scholar]
  17. FarghalyT.A. Al-HasaniW.A. IbrahimM.H. AbdellattifM.H. AbdallahZ.A. Design, synthesis, anticancer activity and docking studies of thiazole linked phenylsulfone moiety as cyclin-dependent kinase 2 (CDK2) inhibitors.Polycycl. Aromat. Compd.20234365001502010.1080/10406638.2022.2097715
     [Google Scholar]
  18. AlosaimyA.M. AbouziedA.S. AlsaediA.M.R. AlafnanA. AlamriA. AlamriM.A. Bin BreakM.K. SabourR. FarghalyT.A. Discovery of novel indene-based hybrids as breast cancer inhibitors targeting Hsp90: Synthesis, bio evaluation and molecular docking study.Arab. J. Chem.20231610456910.1016/j.arabjc.2023.104569
     [Google Scholar]
  19. AlqurashiR.M. FarghalyT.A. SabourR. ShaabanaM.R. Design, synthesis, antimicrobial screening and molecular modeling of novel 6,7 dimethylquinoxalin-2(1H)-one and thiazole derivatives targeting DNA gyrase enzyme.Bioorg. Chem.202313410643310.1016/j.bioorg.2023.10643336842318
     [Google Scholar]
  20. NagendarP. GillespieJ.R. HerbstZ.M. RanadeR.M. MolaskyN.M.R. FaghihO. TurnerR.M. GelbM.H. BucknerF.S. Triazolopyrimidines and imidazopyridines: structure-activity relationships and in vivo efficacy for trypanosomiasis.ACS Med. Chem. Lett.201910110511010.1021/acsmedchemlett.8b0049830655955
     [Google Scholar]
  21. FarghalyT.A. HarrasM.F. AlsaediA.M.R. ThakirH.A. MahmoudH.K. KatowahD.F. Antiviral activity of pyrimidine containing compounds: Patent review.Mini Rev. Med. Chem.202323782185110.2174/138955752366622122014291136545712
     [Google Scholar]
  22. BarradasJ.S. ErreaM.I. D’AccorsoN.B. SepúlvedaC.S. TalaricoL.B. DamonteE.B. Synthesis and antiviral activity of azoles obtained from carbohydrates.Carbohydr. Res.2008343142468247410.1016/j.carres.2008.06.02818692179
     [Google Scholar]
  23. RashidH. MartinesM.A.U. DuarteA.P. JorgeJ. RasoolS. MuhammadR. AhmadN. UmarM.N. Research developments in the syntheses, anti-inflammatory activities and structure–activity relationships of pyrimidines.RSC Advances202111116060609810.1039/D0RA10657G35423143
     [Google Scholar]
  24. DawoodD.H. BatranR.Z. FarghalyT.A. KhedrM.A. AbdullaM.M. New coumarin derivatives as potent selective COX-2 inhibitors; Synthesis, anti-inflammatory, QSAR and molecular modeling studies.Arch. Pharm. Chem. Life Sci.2015875888
     [Google Scholar]
  25. TiperciucB. PârvuA. TamaianR. NastasăC. IonuţI. OnigaO. New anti-inflammatory thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles with antioxidant properties as potential iNOS inhibitors.Arch. Pharm. Res.201336670271410.1007/s12272‑013‑0083‑923504664
     [Google Scholar]
  26. PadmajaA. PayaniT. ReddyG.D. PadmavathiV. Synthesis, antimicrobial and antioxidant activities of substituted pyrazoles, isoxazoles, pyrimidine and thioxopyrimidine derivatives.Eur. J. Med. Chem.200944114557456610.1016/j.ejmech.2009.06.02419631423
     [Google Scholar]
  27. NairN. MajeedJ. PandeyP.K. SweetyR. ThakurR. Antioxidant potential of pyrimidine derivatives against oxidative stress.Indian J. Pharm. Sci.20228411426
     [Google Scholar]
  28. SilvaV.L.M. ElgueroJ. SilvaA.M.S. Current progress on antioxidants incorporating the pyrazole core.Eur. J. Med. Chem.201815639442910.1016/j.ejmech.2018.07.00730015075
     [Google Scholar]
  29. SayedM.T. ElsharabasyS.A. Abdel-AziemA. Synthesis and antimicrobial activity of new series of thiazoles, pyridines and pyrazoles based on coumarin moiety.Sci. Rep.2023131991210.1038/s41598‑023‑36705‑037336955
     [Google Scholar]
  30. MohantyP. BeheraS. BehuraR. ShubhadarshineeL. MohapatraP. BarickA.K. JaliB.R. Antibacterial activity of thiazole and its derivatives: A Review.Biointerface Res. Appl. Chem.20211222171219510.33263/BRIAC122.21712195
     [Google Scholar]
  31. A AlamM. Antibacterial pyrazoles: tackling resistant bacteria.Future Med. Chem.202214534336210.4155/fmc‑2021‑027535050719
     [Google Scholar]
  32. OmarM.A. MasaretG.S. AbbasE.M.H. Abdel-AzizM.M. HarrasM.F. FarghalyT.A. Novel anti-tubercular and antibacterial based benzosuberone-thiazole moieties: Synthesis, molecular docking analysis, DNA gyrase supercoiling and ATPase activity.Bioorg. Chem.202010410431610.1016/j.bioorg.2020.10431633022549
     [Google Scholar]
  33. DawoodD.H. SrourA.M. OmarM.A. FarghalyT.A. El-ShiekhR.A. Synthesis and molecular docking simulation of new benzimidazole–thiazole hybrids as cholinesterase inhibitors.Arch. Pharm. (Weinheim)20243571230020110.1002/ardp.20230020137937360
     [Google Scholar]
  34. LiX. YuY. TuZ. Pyrazole scaffold synthesis, functionalization, and applications in Alzheimer’s disease and Parkinson’s disease treatment (2011–2020).Molecules2021265120210.3390/molecules2605120233668128
     [Google Scholar]
  35. Molecular Operating Environment (MOE)2014Available from: http://www.chemcomp.com
  36. NodzewskaA. BokinaA. RomanowskaK. LaznyR. Environmentally benign diastereoselective synthesis of granatane and tropane aldol derivatives.RSC Advances20144562966810.1039/C4RA02834A
     [Google Scholar]
  37. WoodheadA.J. AngoveH. CarrM.G. ChessariG. CongreveM. CoyleJ.E. CosmeJ. GrahamB. DayP.J. DownhamR. FazalL. FeltellR. FigueroaE. FredericksonM. LewisJ. McMenaminR. MurrayC.W. O’BrienM.A. ParraL. PatelS. PhillipsT. ReesD.C. RichS. SmithD.M. TrewarthaG. VinkovicM. WilliamsB. WoolfordA.J.A. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.J. Med. Chem.201053165956596910.1021/jm100060b20662534
     [Google Scholar]
  38. SaxenaA.K. SaxenaS. ChaudhaeryS.S. Molecular modelling and docking studies on heat shock protein 90 (Hsp90) inhibitors.SAR QSAR Environ. Res.2010211-212010.1080/1062936090356050420373211
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673313163240829094557
Loading
Design, Synthesis, and Docking of Novel Tropane Hybrids as Potent Hsp90 Inhibitors with Potential Anti-Breast Cancer Activity
Curr. Med. Chem. 32, 5070 (2025); https://doi.org/10.2174/0109298673313163240829094557
/content/journals/cmc/10.2174/0109298673313163240829094557
/content/journals/cmc/10.2174/0109298673313163240829094557
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): anticancer activity; breast cancer; docking study; Hsp90; synthesis; tropane

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