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  4. Volume 21, Issue 14
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Volume 21, Issue 14
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

As cancer stands as a significant global health concern, many heterocyclic compounds that are more effective in cancer cells than healthy cells are being investigated for their selective anticancer potentials. One such compound is fenretinide, a synthetic derivative of retinoic acid that has a broad spectrum of cytotoxic activity against primary tumor cells, cell lines, and/or xenografts of various cancers. In this context, bexarotene and its derivatives, synthesized from hybridization of the fenretinide, are expected to possess a potential anticancer activity.

Objective

The objective of the present study was to investigate the synthesis of novel amid-derived and bexarotene-based compounds, as well as to assess their cytotoxic effects in different cancer cell lines.

Methods

This study involved the synthesis of twelve novel retinoid derivatives () in a six-step process. The cytotoxic activities of these compounds were assessed against various cancer cell lines, such as A549 (human lung carcinoma), HeLa (human cervical cancer), MCF7 (human breast adenocarcinoma), and WiDr (human colon adenocarcinoma). The chemical structures of these compounds were elucidated through their elemental analysis, mass spectrometry (ESI+, ESI-), as well as 1H-NMR and 13C-NMR spectroscopic data.

Results

The obtained cell toxicity results indicated that compounds and were found to exhibit the strongest cytotoxic activity in above mentioned cancer cell lines. The IC values for active compounds, and were determined as 2.38µM and 2.29µM, respectively. Remarkably, these compounds displayed higher cytotoxic activity in the WiDr cell line related to positive control, camptothecin (CPT). Moreover, compounds and demonstrated very similar level of cytotoxic activity to CPT, indicating their potential for antitumoral applications upon further studies.

Conclusion

While compounds 11, 12, 14, and 17 indicated a very comparable anticancer activity to CPT, compounds 6, 8, 11 and 12 showed more selective anticancer effect against cancer cells than non-cancerous cells. In accordance with the findings of the present study, they can be evaluated as primary candidates for further studies, specifically as RXRα-targeted anticancer agents.

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2024-11-01
2024-11-19

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References

  1. BrayF. LaversanneM. WeiderpassE. SoerjomataramI. The ever‐increasing importance of cancer as a leading cause of premature death worldwide.Cancer2021127163029303010.1002/cncr.33587 34086348
     [Google Scholar]
  2. MotamediM. ChehadeA. SangheraR. GrewalP. A clinician’s guide to topical retinoids.J. Cutan. Med. Surg.2022261717810.1177/12034754211035091 34292058
     [Google Scholar]
  3. SanzM.J. AlbertosF. OteroE. JuezM. MorcilloE.J. PiquerasL. Retinoid X receptor agonists impair arterial mononuclear cell recruitment through peroxisome proliferator-activated receptor-γ activation.J. Immunol.2012189141142410.4049/jimmunol.1102942 22661092
     [Google Scholar]
  4. GermainP. ChambonP. EicheleG. EvansR.M. LazarM.A. LeidM. De LeraA.R. LotanR. MangelsdorfD.J. GronemeyerH. International union of pharmacology. LX. Retinoic acid receptors.Pharmacol. Rev.200658471272510.1124/pr.58.4.4 17132850
     [Google Scholar]
  5. CazzanigaM. VarricchioC. MontefrancescoC. FeroceI. Guerrieri-GonzagaA. Fenretinide (4-HPR): a preventive chance for women at genetic and familial risk?J. Biomed. Biotechnol.201220121910.1155/2012/172897 22500077
     [Google Scholar]
  6. de LeraA.R. BourguetW. AltucciL. GronemeyerH. Design of selective nuclear receptor modulators: RAR and RXR as a case study.Nat. Rev. Drug Discov.200761081182010.1038/nrd2398 17906643
     [Google Scholar]
  7. GudasL.J. TangX.H. KwameO. SurvalekA. Combination therapy for head and neck cancer.U. S. Patent PCT/US2015/019528, March 092015
  8. TangX.H. Osei-SarfoK. UrvalekA.M. ZhangT. ScognamiglioT. GudasL.J. Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide.Proc. Natl. Acad. Sci. USA2014111248907891210.1073/pnas.1404828111 24927566
     [Google Scholar]
  9. WagnerC.E. JurutkaP.W. MarshallP.A. GroyT.L. van der VaartA. ZillerJ.W. FurmickJ.K. GraeberM.E. MatroE. MiguelB.V. TranI.T. KwonJ. TedeschiJ.N. MoosaviS. DanishyarA. PhilpJ.S. KhameesR.O. JacksonJ.N. GrupeD.K. BadshahS.L. HartJ.W. Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).J. Med. Chem.200952195950596610.1021/jm900496b 19791803
     [Google Scholar]
  10. KelloffG.J. CrowellJ.A. BooneC.W. SteeleV.E. LubetR.A. GreenwaldP. AlbertsD.S. CoveyJ.M. DoodyL.A. KnappG.G. NayfieldS. ParkinsonD.R. PrasadV.K. ProrokP.C. SausvilleE.A. SigmanC.C. Chemoprevention Branch and Agent Development Committee. National Cancer Institute. Strategy and planning for chemopreventive drug development: Clinical development plans.J. Cell. Biochem.199456S20556210.1002/jcb.240560906 7616753
     [Google Scholar]
  11. CobleighM.A. DowlatshahiK. DeutschT.A. MehtaR.G. MoonR.C. MinnF. BensonA.B.III RademakerA.W. AshenhurstJ.B. WadeJ.L. III Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer.J. Clin. Oncol.199311347447710.1200/JCO.1993.11.3.474 8445423
     [Google Scholar]
  12. ModianoM.R. DaltonW.S. LippmanS.M. JoffeL. BoothA.R. MeyskensF.L. Jr Phase II study of Fenretinide (N-[4-Hydroxyphenyl]retinamide) in advanced breast cancer and melanoma.Invest. New Drugs19908331731910.1007/BF00171846 2148744
     [Google Scholar]
  13. UlukayaE. PirianovG. KurtM.A. WoodE.J. MehmetH. Fenretinide induces cytochrome c release, caspase 9 activation and apoptosis in the absence of mitochondrial membrane depolarisation.Cell Death Differ.200310785685910.1038/sj.cdd.4401242 12815470
     [Google Scholar]
  14. SimeoneA.M. EkmekciogluS. BroemelingL.D. GrimmE.A. TariA.M. A novel mechanism by which N-(4-hydroxyphenyl) retinamide inhibits breast cancer cell growth: the production of nitric oxide.Mol. Cancer Ther.200211210091017 12481423
     [Google Scholar]
  15. OhlmannC.H. JungC. JaquesG. Is growth inhibition and induction of apoptosis in lung cancer cell lines by fenretinide [N-(4-hydroxyphenyl)retinamide] sufficient for cancer therapy?Int. J. Cancer2002100552052610.1002/ijc.10525 12124800
     [Google Scholar]
  16. AppiertoV. TiberioP. VillaniM.G. CavadiniE. FormelliF. PLAB induction in fenretinide-induced apoptosis of ovarian cancer cells occurs via a ROS-dependent mechanism involving ER stress and JNK activation.Carcinogenesis200930582483110.1093/carcin/bgp067 19325135
     [Google Scholar]
  17. MessnerM.C. CabotM.C. Cytotoxic responses to N-(4-hydroxyphenyl)retinamide in human pancreatic cancer cells.Cancer Chemother. Pharmacol.201168247748710.1007/s00280‑010‑1504‑9 21072519
     [Google Scholar]
  18. LiX. LingW. PennisiA. KhanS. YaccobyS. Fenretinide inhibits myeloma cell growth, osteoclastogenesis and osteoclast viability.Cancer Lett.2009284217518110.1016/j.canlet.2009.04.022 19446953
     [Google Scholar]
  19. ReynoldsC.P. MatthayK.K. VillablancaJ.G. MaurerB.J. Retinoid therapy of high-risk neuroblastoma.Cancer Lett.20031971-218519210.1016/S0304‑3835(03)00108‑3 12880980
     [Google Scholar]
  20. Claudio Viegas-Junior,; Danuello, A.; da Silva Bolzani, V.; Barreiro, E.J.; Fraga, C.A. Molecular hybridization: a useful tool in the design of new drug prototypes.Curr. Med. Chem.200714171829185210.2174/092986707781058805 17627520
     [Google Scholar]
  21. BoehmM.F. HeymanR.A. Compounds having selective activity for retinoid x receptors, and means for modulation of processes mediated by retinoid X receptors.European Patent EP0678087B1, March 17,1999
  22. VichaiV. KirtikaraK. Sulforhodamine B colorimetric assay for cytotoxicity screening.Nat. Protoc.2006131112111610.1038/nprot.2006.179 17406391
     [Google Scholar]
  23. IndrayantoG. PutraG.S. SuhudF. Validation of in-vitro bioassay methods: Application in herbal drug research.Profiles Drug Subst. Excip. Relat. Methodol.20214627330710.1016/bs.podrm.2020.07.005 33461699
     [Google Scholar]
  24. DobrotkovaV. ChlapekP. MazanekP. SterbaJ. VeselskaR. Traffic lights for retinoids in oncology: molecular markers of retinoid resistance and sensitivity and their use in the management of cancer differentiation therapy.BMC Cancer2018181105910.1186/s12885‑018‑4966‑5 30384831
     [Google Scholar]
  25. LiY. ZhangY. HillJ. ShenQ. KimH.T. XuX. HilsenbeckS.G. BissonnetteR.P. LamphW.W. BrownP.H. The Rexinoid LG100268 prevents the development of preinvasive and invasive estrogen receptor negative tumors in MMTV-erbB2 mice.Clin. Cancer Res.200713206224623110.1158/1078‑0432.CCR‑06‑2681 17947490
     [Google Scholar]
  26. CaoM. RoyceD.B. RisingsongR. WilliamsC.R. SpornM.B. LibyK.T. The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice.Cancer Prev. Res. (Phila.)20169110511410.1158/1940‑6207.CAPR‑15‑0325 26554632
     [Google Scholar]
  27. MoerlandJ.A. ZhangD. ReichL.A. CarapellucciS. LockwoodB. LealA.S. Krieger-BurkeT. AleiwiB. EllsworthE. LibyK.T. The novel rexinoid MSU-42011 is effective for the treatment of preclinical Kras-driven lung cancer.Sci. Rep.20201012224410.1038/s41598‑020‑79260‑8 33335263
     [Google Scholar]
  28. HaciogluC. KarF. KacarS. SahinturkV. KanbakG. Bexarotene inhibits cell proliferation by inducing oxidative stress, DNA damage and apoptosis via PPARγ/NF-κB signaling pathway in C6 glioma cells.Med. Oncol.20213833110.1007/s12032‑021‑01476‑z 33599853
     [Google Scholar]
  29. KeepersY.P. PizaoP.E. PetersG.J. van Ark-OtteJ. WinogradB. PinedoH.M. Comparison of the sulforhodamine B protein and tetrazolium (MTT) assays for in vitro chemosensitivity testing.Eur. J. Cancer Clin. Oncol.199127789790010.1016/0277‑5379(91)90142‑Z 1834124
     [Google Scholar]
  30. BalaramanS. NayakN. SubbiahM. ElangoK.P. Synthesis and antiviral study of novel 4-(2-(6-amino-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyrimidin-3-yl)ethyl)benzamide derivatives.Med. Chem. Res.20182711-122538254610.1007/s00044‑018‑2256‑z
     [Google Scholar]
  31. GujaratiN.A. ZengL. GuptaP. ChenZ.S. KorliparaV.L. Design, synthesis and biological evaluation of benzamide and phenyltetrazole derivatives with amide and urea linkers as BCRP inhibitors.Bioorg. Med. Chem. Lett.201727204698470410.1016/j.bmcl.2017.09.009 28916341
     [Google Scholar]
  32. KaurA. PathakD.P. SharmaV. NarasimhanB. SharmaP. MathurR. WakodeS. Synthesis, biological evaluation and docking study of N-(2-(3,4,5-trimethoxybenzyl)benzoxazole-5-yl) benzamide derivatives as selective COX-2 inhibitor and anti-inflammatory agents.Bioorg. Chem.20188119120210.1016/j.bioorg.2018.07.007 30138907
     [Google Scholar]
  33. LuK. CaiL. ZhangX. WuG. XuC. ZhaoY. GongP. Design, synthesis, and biological evaluation of novel substituted benzamide derivatives bearing a 1,2,3-triazole moiety as potent human dihydroorotate dehydrogenase inhibitors.Bioorg. Chem.20187652853710.1016/j.bioorg.2017.12.025 29316525
     [Google Scholar]
  34. PerinN. RoškarićP. SovićI. BočekI. StarčevićK. HranjecM. VianelloR. Amino-substituted benzamide derivatives as promising antioxidant agents: A combined experimental and computational study.Chem. Res. Toxicol.201831997498410.1021/acs.chemrestox.8b00175 30109922
     [Google Scholar]
  35. ThirumuruganK. LakshmananS. GovindarajD. Daniel PrabuD.S. RamalakshmiN. Arul AntonyS. Design, synthesis and anti-inflammatory activity of pyrimidine scaffold benzamide derivatives as epidermal growth factor receptor tyrosine kinase inhibitors.J. Mol. Struct.2018117154155010.1016/j.molstruc.2018.06.003
     [Google Scholar]
  36. VandyckK. RomboutsG. StoopsB. TahriA. VosA. VerschuerenW. WuY. YangJ. HouF. HuangB. VergauwenK. DehertoghP. BerkeJ.M. RaboissonP. Synthesis and Evaluation of N -Phenyl-3-sulfamoyl-benzamide Derivatives as Capsid Assembly Modulators Inhibiting Hepatitis B Virus (HBV).J. Med. Chem.201861146247626010.1021/acs.jmedchem.8b00654 29906396
     [Google Scholar]
  37. WeiM. PengX. XingL. DaiY. HuangR. GengM. ZhangA. AiJ. SongZ. Design, synthesis and biological evaluation of a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent fibroblast growth factor receptor (FGFR) inhibitors.Eur. J. Med. Chem.201815492810.1016/j.ejmech.2018.05.005 29775937
     [Google Scholar]
  38. ArnoM.C. SimpsonJ.D. BlackmanL.D. BranniganR.P. ThurechtK.J. DoveA.P. Enhanced drug delivery to cancer cells through a pH-sensitive polycarbonate platform.Biomater. Sci.202311390891510.1039/D2BM01626E 36533676
     [Google Scholar]
  39. IstivanT.S. PirogovaE. GanE. AlmansourN.M. ColoeP.J. CosicI. Biological effects of a de novo designed myxoma virus peptide analogue: evaluation of cytotoxicity on tumor cells.PLoS One201169e2480910.1371/journal.pone.0024809 21949758
     [Google Scholar]
  40. RathK.S. NaiduS.K. LataP. BidH.K. RiveraB.K. McCannG.A. TierneyB.J. ElNaggarA.C. BravoV. LeoneG. HoughtonP. HidegK. KuppusamyP. CohnD.E. SelvendiranK. HO-3867, a safe STAT3 inhibitor, is selectively cytotoxic to ovarian cancer.Cancer Res.20147482316232710.1158/0008‑5472.CAN‑13‑2433 24590057
     [Google Scholar]
  41. OkadaJ. SunagaN. YamadaE. SaitoT. OzawaA. NakajimaY. OkadaK. PessinJ.E. OkadaS. YamadaM. FAM83G is a novel inducer of apoptosis.Molecules20202512281010.3390/molecules25122810 32570757
     [Google Scholar]
  42. Hardman, J.G.; Limbird, L.E., The Pharmacological Basis of Therapeutics.10th edNew YorkMcGraw-Hill2001
     [Google Scholar]
  43. KochA. TamezP. PezzutoJ. SoejartoD. Evaluation of plants used for antimalarial treatment by the Maasai of Kenya.J. Ethnopharmacol.20051011-3959910.1016/j.jep.2005.03.011 15878245
     [Google Scholar]
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Design, Synthesis, and Biological Evaluation of Some Novel Retinoid Derivatives
Letters in Drug Design & Discovery 21, 2926 (2024); https://doi.org/10.2174/0115701808243556231017055256
/content/journals/lddd/10.2174/0115701808243556231017055256
/content/journals/lddd/10.2174/0115701808243556231017055256
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  • Article Type:     Research Article
Keyword(s): anticancer; Bexarotene; cytotoxicity; hybrid molecules; retinoid; RXRa

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