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2000
Volume 25, Issue 20
  • ISSN: 1871-5206
  • E-ISSN: 1875-5992

Abstract

Background

Monastrol is a known kinesin Eg5 inhibitor. It is a dihydropyrimidine with 4-(m-hydroxyphenyl) substituent. In contrast to taxols and vinca alkaloids, which, through targeting microtubules, affect both normal and cancer cells, kinesin inhibitors selectively target cancer cells.

Objectives

In this study, -hydroxyphenyl in monastrol was replaced with imidazolyl substituent, which has better water solubility and is found in the structure of many drugs and biologically active compounds. The effects of synthesized compounds were also investigated.

Methods

Three series of monastrol-related dihydropyrimidinone derivatives were synthesized through a modified Biginelli reaction. The newly synthesized compounds were characterized by elemental analysis, LCMS, and NMR. Then, the structure-activity relationship (SAR) of synthesized compounds was evaluated by their toxicity, molecular docking scores, and results of molecular dynamic simulation. The compounds with more potential (, , and ) were further investigated and for their anti-cancer effects.

Results

The synthesized compounds could effectively reduce the ATPase activity of kinesins, which was consistent with the observation of G2/M arrest of cells in flow cytometry and confocal microscopy results. In addition, an increase in cells in the sub-G1 phase, along with the enhancement of the Bax/Bcl-2 ratio and overexpression of caspases 3, 9, and 8, suggested the apoptosis-inducing effects of compounds. Moreover, compounds showed potent anti-angiogenic effects altering the expression of genes involved in angiogenesis, which was consistent with the reduced length of capillaries in the CAM test. The synthesized compounds could also demonstrate satisfactory results in the mice tumor model, which was in accordance with the findings of experiments.

Conclusion

Novel dihydropyrimidinone derivatives synthesized modified Biginelli reaction present promising potential as anti-cancer agents.

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2025-12-18

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References

  1. HiranoT. Chromosome dynamics during mitosis.Cold Spring Harb. Perspect. Biol.201576a01579210.1101/cshperspect.a015792 25722466
     [Google Scholar]
  2. MaiatoH. GomesA. SousaF. BarisicM. Mechanisms of chromosome congression during mitosis.Biology2017611310.3390/biology6010013 28218637
     [Google Scholar]
  3. PetryS. Mechanisms of mitotic spindle assembly.Annu. Rev. Biochem.201685165968310.1146/annurev‑biochem‑060815‑014528 27145846
     [Google Scholar]
  4. TolićI.M. PavinN. Mitotic spindle: Lessons from theoretical modeling.Mol. Biol. Cell202132321822210.1091/mbc.E20‑05‑0335 33507108
     [Google Scholar]
  5. JiangC. YouQ. Kinesin spindle protein inhibitors in cancer: A patent review (2008 - present).Expert Opin. Ther. Pat.201323121547156010.1517/13543776.2013.833606 23978071
     [Google Scholar]
  6. YildizA. Mechanism and regulation of kinesin motors.Nat. Rev. Mol. Cell Biol.20241118 39394463
     [Google Scholar]
  7. KapiteinL.C. PetermanE.J. Single molecule experiments and the kinesin motor protein superfamily: Walking hand in hand.Cambridge, USSingle Molecule Biology2009356010.1016/B978‑0‑12‑374227‑8.00002‑X
     [Google Scholar]
  8. NejabatM. HadizadehF. Sahebkar ajcric, pharmacology epfcc. the application of kinesin inhibitors in medical issues.Curr. Rev. Clin. Exper. Pharma. Forme. Curr. Clin. Pharma.202419437037810.2174/0127724328277623231204064614
     [Google Scholar]
  9. KamalA. MalikS.M. BajeeS. AzeezaS. FaazilS. RamakrishnaS. NaiduV.G.M. VishnuwardhanM.V.P.S. Synthesis and biological evaluation of conformationally flexible as well as restricted dimers of monastrol and related dihydropyrimidones.Eur. J. Med. Chem.20114683274328110.1016/j.ejmech.2011.04.048 21620531
     [Google Scholar]
  10. ChanK. KohC.G. LiH. Mitosis-targeted anti-cancer therapies: Where they stand.Cell Death Dis.2012310e411e41110.1038/cddis.2012.148
     [Google Scholar]
  11. ShahinR. AljamalS. Kinesin spindle protein inhibitors in cancer: From high throughput screening to novel therapeutic strategies.Future Sci. OA202283FSO77810.2144/fsoa‑2021‑0116 35251692
     [Google Scholar]
  12. SarliV. GiannisA. Inhibitors of mitotic kinesins: Next-generation antimitotics.ChemMedChem20061329329810.1002/cmdc.200500045 16892362
     [Google Scholar]
  13. ShaoY.Y. SunN.Y. JengY.M. WuY.M. HsuC. HsuC.H. HsuH.C. ChengA.L. LinZ.Z. Eg5 as a prognostic biomarker and potential therapeutic target for hepatocellular carcinoma.Cells2021107169810.3390/cells10071698 34359867
     [Google Scholar]
  14. MarconiG.D. CarradoriS. RicciA. GuglielmiP. CataldiA. ZaraS. Kinesin Eg5 targeting inhibitors as a new strategy for gastric adenocarcinoma treatment.Molecules20192421394810.3390/molecules24213948 31683688
     [Google Scholar]
  15. El-NassanH.B. Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents.Eur. J. Med. Chem.20136261463110.1016/j.ejmech.2013.01.031 23434636
     [Google Scholar]
  16. HegdeP. CogswellJ. CarrickK. JacksonJ. WoodK. EngW. Differential gene expression analysis of kinesin spindle protein in human solid tumors.Proc. Am. Soc. Clin. Oncol.200322535
     [Google Scholar]
  17. DingS. XingN. LuJ. ZhangH. NishizawaK. LiuS. YuanX. QinY. LiuY. OgawaO. NishiyamaH. Overexpression of Eg5 predicts unfavorable prognosis in non‐muscle invasive bladder urothelial carcinoma.Int. J. Urol.201118643243810.1111/j.1442‑2042.2011.02751.x 21449971
     [Google Scholar]
  18. Vuurenv.R.J. VisagieM.H. TheronA.E. JoubertA.M. Antimitotic drugs in the treatment of cancer.Cancer Chemother. Pharmacol.20157661101111210.1007/s00280‑015‑2903‑8 26563258
     [Google Scholar]
  19. SwellmeenL. ShahinR. Al-HiariY. AlamiriA. HasanA. ShaheenO. Structure based drug design of Pim-1 kinase followed by pharmacophore guided synthesis of quinolone-based inhibitors.Bioorg. Med. Chem.201725174855487510.1016/j.bmc.2017.07.036 28760531
     [Google Scholar]
  20. MayerT.U. KapoorT.M. HaggartyS.J. KingR.W. SchreiberS.L. MitchisonT.J. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen.Science1999286544197197410.1126/science.286.5441.971 10542155
     [Google Scholar]
  21. MarquesL.A. SemprebonS.C. NiwaA.M. D’EpiroG.F.R. SartoriD. FátimadÂ. RibeiroL.R. MantovaniM.S. Antiproliferative activity of monastrol in human adenocarcinoma (MCF-7) and non-tumor (HB4a) breast cells.Naunyn Schmiedebergs Arch. Pharmacol.2016389121279128810.1007/s00210‑016‑1292‑9 27592117
     [Google Scholar]
  22. AshamH. BohlooliS. DostkamelD. RezvanpoorS. SepehriS. Design, synthesis, and biological screening for cytotoxic activity of monastrol analogues.Polycycl. Aromat. Compd.20224284863487710.1080/10406638.2021.1913424
     [Google Scholar]
  23. SafariS. GhavimiR. Razzaghi-AslN. SepehriS. Synthesis, biological evaluation and molecular docking study of dihydropyrimidine derivatives as potential anticancer agents.J. Heterocycl. Chem.20205731023103310.1002/jhet.3822
     [Google Scholar]
  24. TawfikH.O. El-MoselhyT.F. El-DinN.S. El-HamamsyM.H. Design, synthesis, and bioactivity of dihydropyrimidine derivatives as kinesin spindle protein inhibitors.Bioorg. Med. Chem.2019272311512610.1016/j.bmc.2019.115126 31648875
     [Google Scholar]
  25. NikamD. JainA. Advances in the discovery of DHPMs as Eg5 inhibitors for the management of breast cancer and glioblastoma: A review.Results Chem.2023510071810.1016/j.rechem.2022.100718
     [Google Scholar]
  26. RostamiM. BidramZ. SirousH. KhodarahmiG.A. HassanzadehF. DanaN. HaririA.A. Monastrol derivatives: in silico and in vitro cytotoxicity assessments.Res. Pharm. Sci.202015324926210.4103/1735‑5362.288427 33088325
     [Google Scholar]
  27. RagabF.A.F. Abou-SeriS.M. Abdel-AzizS.A. AlfayomyA.M. AboelmagdM. Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety.Eur. J. Med. Chem.201713814015110.1016/j.ejmech.2017.06.026 28667871
     [Google Scholar]
  28. MatiasM. CamposG. SantosA.O. FalcãoA. SilvestreS. AlvesG. Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones.Arab. J. Chem.20191285086510210.1016/j.arabjc.2016.12.007
     [Google Scholar]
  29. JahaniM. AkaberiM. HeidariT. KamaliH. NejabatM. RajabiO. HadizadehF. Simultaneous determination of mometasone furoate and calcipotriol in a binary mixture by validated HPLC and chemometric-assisted UV spectrophotometric methods and identification of degradation products by LC-MS.Iran. J. Basic Med. Sci.20232613747 36594065
     [Google Scholar]
  30. AbnousK. BaratiB. MehriS. FarimaniM.M.R. AlibolandiM. MohammadpourF. GhandadiM. HadizadehF. Synthesis and molecular modeling of six novel monastrol analogues: Evaluation of cytotoxicity and kinesin inhibitory activity against HeLa cell line.Daru20132117010.1186/2008‑2231‑21‑70 24355209
     [Google Scholar]
  31. PashaeiH. RouhaniA. NejabatM. HadizadehF. MirzaeiS. NadriH. MalekiM.F. GhodsiR. Synthesis and molecular dynamic simulation studies of novel N-(1-benzylpiperidin-4-yl) quinoline-4-carboxamides as potential acetylcholinesterase inhibitors.J. Mol. Struct.2021124413091910.1016/j.molstruc.2021.130919
     [Google Scholar]
  32. SunH. JiaJ. WangX. MaB. DiL. SongG. RenJ. CD44+/CD24− breast cancer cells isolated from MCF-7 cultures exhibit enhanced angiogenic properties.Clin. Transl. Oncol.2013151465410.1007/s12094‑012‑0891‑2 22855175
     [Google Scholar]
  33. GuidoB.C. RamosL.M. NolascoD.O. NobregaC.C. AndradeB.Y.G. Pic-TaylorA. NetoB.A.D. CorrêaJ.R. Impact of kinesin Eg5 inhibition by 3,4-dihydropyrimidin-2(1H)-one derivatives on various breast cancer cell features.BMC Cancer201515128310.1186/s12885‑015‑1274‑1 25885813
     [Google Scholar]
  34. AnchanH.N. C, N.P.; Bhat, N.S.; Kumari, M.; Dutta, S. Efficient synthesis of novel biginelli and hantzsch products sourced from biorenewable furfurals using gluconic acid aqueous solution as the green organocatalyst.ACS Omega2023837340773408310.1021/acsomega.3c05106 37744814
     [Google Scholar]
  35. NejabatM. GhodsiR. HadizadehF. Coumarins and quinolones as effective multiple targeted agents versus Covid-19: An in silico study.Med. Chem.202218222023710.2174/1573406417666210208223924 33563156
     [Google Scholar]
  36. NejabatM. KalaniM.R. NejabatM. HadizadehF. Molecular dynamic and in vitro evaluation of chitosan/tripolyphosphate nanoparticles as an insulin delivery system at two different pH values.J. Biomol. Struct. Dyn.20224020101531016110.1080/07391102.2021.1940280 34154515
     [Google Scholar]
  37. NejabatM. SoltaniF. AlibolandiM. NejabatM. AbnousK. HadizadehF. RamezaniM. Smac peptide and doxorubicin-encapsulated nanoparticles: Design, preparation, computational molecular approach and in vitro studies on cancer cells.J. Biomol. Struct. Dyn.202240280781910.1080/07391102.2020.1819420 32912085
     [Google Scholar]
  38. Atapour-MashhadH. SoukhtanlooM. GolmohammadzadehS. ChamaniJ. NejabatM. HadizadehF. Synthesis and molecular dynamic simulation of novel cationic and non-cationic pyrimidine derivatives as potential G-quadruplex-ligands.Anticancer. Agents Med. Chem.202424151126114110.2174/0118715206291797240523112439 38840398
     [Google Scholar]
  39. NejabatM. HadizadehF. NejabatM. RajabiO. Novel hits for autosomal dominated polycystic kidney disease (ADPKD) targeting derived by in silico screening on ZINC-15 natural product database.J. Biomol. Struct. Dyn.202442288590210.1080/07391102.2023.2196700 37029756
     [Google Scholar]
  40. PanW. ZhangG. Linalool monoterpene exerts potent antitumor effects in OECM 1 human oral cancer cells by inducing sub-G1 cell cycle arrest, loss of mitochondrial membrane potential and inhibition of PI3K/AKT biochemical pathway.JBUON2019241323328 30941988
     [Google Scholar]
  41. LiuS. ZhaoY. CuiH.F. CaoC.Y. ZhangY.B. 4-terpineol exhibits potent in vitro and in vivo anticancer effects in Hep-G2 hepatocellular carcinoma cells by suppressing cell migration and inducing apoptosis and sub-G1 cell cycle arrest.J. Balkan Union Oncol.201621511951202 27837623
     [Google Scholar]
  42. ZengQ. YiH. HuangL. AnQ. WangH. Long-term arsenite exposure induces testicular toxicity by redox imbalance, G2/M cell arrest and apoptosis in mice.Toxicology201941112213210.1016/j.tox.2018.09.010 30278210
     [Google Scholar]
  43. LiL. MaN. ZhouH. WangQ. ZhangH. WangP. HouH. WenH. GaoF. Zinc oxide nanoparticles-induced epigenetic change and G2/M arrest are associated with apoptosis in human epidermal keratinocytes.Int. J. Nanomed.2016113859387410.2147/IJN.S107021 27570453
     [Google Scholar]
  44. PanZ. ZhangX. YuP. ChenX. LuP. LiM. LiuX. LiZ. WeiF. WangK. ZhengQ. LiD. Cinobufagin induces cell cycle arrest at the G2/M phase and promotes apoptosis in malignant melanoma cells.Front. Oncol.2019985310.3389/fonc.2019.00853 31552178
     [Google Scholar]
  45. ZhuL. HanM.B. GaoY. WangH. DaiL. WenY. NaL.X. Curcumin triggers apoptosis via upregulation of Bax/Bcl-2 ratio and caspase activation in SW872 human adipocytes.Mol. Med. Rep.20151211151115610.3892/mmr.2015.3450 25760477
     [Google Scholar]
  46. BergandiL. MungoE. MoroneR. BoscoO. RolandoB. DoublierS. Hyperglycemia promotes chemoresistance through the reduction of the mitochondrial DNA damage, the Bax/Bcl-2 and Bax/Bcl-XL ratio, and the cells in Sub-G1 phase due to antitumoral drugs induced-cytotoxicity in human colon adenocarcinoma cells.Front. Pharmacol.2018986610.3389/fphar.2018.00866 30150934
     [Google Scholar]
  47. ChipukJ.E. FisherJ.C. DillonC.P. KriwackiR.W. KuwanaT. GreenD.R. Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins.Proc. Natl. Acad. Sci. USA200810551203272033210.1073/pnas.0808036105 19074266
     [Google Scholar]
  48. EdlichF. BCL-2 proteins and apoptosis: Recent insights and unknowns.Biochem. Biophys. Res. Commun.20185001263410.1016/j.bbrc.2017.06.190 28676391
     [Google Scholar]
  49. LiuZ. DingY. YeN. WildC. ChenH. ZhouJ. Direct activation of Bax protein for cancer therapy.Med. Res. Rev.201636231334110.1002/med.21379 26395559
     [Google Scholar]
  50. NejabatM. EisvandF. SoltaniF. AlibolandiM. TaghdisiM.S. AbnousK. HadizadehF. RamezaniM. Combination therapy using Smac peptide and doxorubicin-encapsulated MUC 1-targeted polymeric nanoparticles to sensitize cancer cells to chemotherapy: An in vitro and in vivo study.Int. J. Pharm.202058711965010.1016/j.ijpharm.2020.119650 32679263
     [Google Scholar]
  51. VijapurkarU. WangW. HerbstR. Potentiation of kinesin spindle protein inhibitor-induced cell death by modulation of mitochondrial and death receptor apoptotic pathways.Cancer Res.200767123724510.1158/0008‑5472.CAN‑06‑2406 17210704
     [Google Scholar]
  52. TaoW. SouthV.J. DiehlR.E. DavideJ.P. Sepp-LorenzinoL. FraleyM.E. ArringtonK.L. LobellR.B. An inhibitor of the kinesin spindle protein activates the intrinsic apoptotic pathway independently of p53 and de novo protein synthesis.Mol. Cell. Biol.200727268969810.1128/MCB.01505‑06 17101792
     [Google Scholar]
  53. TaoW. SouthV.J. ZhangY. DavideJ.P. FarrellL. KohlN.E. Sepp-LorenzinoL. LobellR.B. Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage.Cancer Cell200581495910.1016/j.ccr.2005.06.003 16023598
     [Google Scholar]
  54. IuliisD.F. TaglieriL. SalernoG. GiuffridaA. MilanaB. GiantulliS. CarradoriS. SilvestriI. ScarpaS. RETRACTED ARTICLE: The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells.Invest. New Drugs201634439940610.1007/s10637‑016‑0345‑8 26994617
     [Google Scholar]
  55. CeciC. AtzoriM.G. LacalP.M. GrazianiG. Role of VEGFs/VEGFR-1 signaling and its inhibition in modulating tumor invasion: Experimental evidence in different metastatic cancer models.Int. J. Mol. Sci.2020214138810.3390/ijms21041388 32085654
     [Google Scholar]
  56. BałanB.J. SłotwińskiR. VEGF and tumor angiogenesis.Cent. Eur. J. Immunol.200833416
     [Google Scholar]
  57. SatohN. YamadaY. KinugasaY. TakakuraN. Angiopoietin‐1 alters tumor growth by stabilizing blood vessels or by promoting angiogenesis.Cancer Sci.200899122373237910.1111/j.1349‑7006.2008.00961.x 19018775
     [Google Scholar]
  58. StoeltzingO. AhmadS.A. LiuW. McCartyM.F. WeyJ.S. ParikhA.A. FanF. ReinmuthN. KawaguchiM. BucanaC.D. EllisL.M. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors.Cancer Res.2003631233703377 12810673
     [Google Scholar]
  59. AhmadS.A. LiuW. JungY.D. FanF. WilsonM. ReinmuthN. ShaheenR.M. BucanaC.D. EllisL.M. The effects of angiopoietin-1 and -2 on tumor growth and angiogenesis in human colon cancer.Cancer Res.200161412551259 11245414
     [Google Scholar]
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Novel Dihydropyrimidinones Synthesized through Modified Biginelli Reaction as Eg5 Kinesin Inhibitors with Potential Anti-cancer Effects: In vitro and In vivo Studies
Anti-Cancer Agents in Medicinal Chemistry 25, 1622 (2025); https://doi.org/10.2174/0118715206373183250324063523
/content/journals/acamc/10.2174/0118715206373183250324063523
/content/journals/acamc/10.2174/0118715206373183250324063523
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  • Article Type:     Research Article
Keyword(s): ATPase; cancer therapy; cell cycle arrest; dihydropyrimidinone; Eg5 kinesin; Monastrol

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