Synthesis, molecular modeling, in vivo study and anticancer activity against prostate cancer of (+) (S)-naproxen derivatives

Basit Öğe Kaydı
dc.contributor.authorBirgül, Kaan
dc.contributor.authorYıldırım, Yeliz
dc.contributor.authorKarasulu, H.Yeşim
dc.contributor.authorKarasulu, Ercüment
dc.contributor.authorUba, Abdullah İbrahim
dc.contributor.authorYelekçi, Kemal
dc.contributor.authorKüçükgüzel, Ş.Güniz
dc.contributor.authorCumaoğlu, Ahmet
dc.contributor.authorKabasakal, Levent
dc.contributor.authorYılmaz, Özgür
dc.date.accessioned2021-05-15T12:49:29Z
dc.date.available2021-05-15T12:49:29Z
dc.date.issued2020
dc.departmentEczacılık Fakültesi, Farmasötik Kimya Anabilim Dalıen_US
dc.description.abstractIn this study, (S)-naproxen thiosemicarbazides (3a-d), 1,2,4-triazoles (4a-c), triazole-thioether hybride compounds (5a-p) were synthesized and their structures (3a, 3d, 4a and 5a-p) were confirmed by FT-IR, 1H NMR,13C NMR, HR-Mass spectra and elemental analysis. These compounds are designed to inhibit methionine amino peptidase-2 (MetAP2) enzyme in prostate cancer. These compounds (3d, 5a-p) evaluated against androgen-independent prostate adenocarcinoma (PC-3, DU-145) and androgen-dependent prostate adenocarcinoma (LNCaP) cell lines by using MTS method. Compounds 5a, 5b, 5d and 5e showed 14.2, 5.8, 10.8 and 8.4 ?M anticancer activity against PC-3 cell lines, compounds 5e, 5g and 5n presented anticancer activity against DU-145 cell lines 18.8, 12.25 and 10.2 ?M, and compounds 5g, 5m and 5n exhibited anticancer activity against LNCaP cell lines 12.25, 22.76 and 2.21 ?M, respectively. Consequently, of these results, compounds 5e and 5n showed the highest activities against androgen dependent and independent prostate cancer cell lines, so these compounds could be potent small molecules against prostate cancer. Furthermore, mitogen-activated protein kinase (MAPK) pathway activation, AKT (protein kinase B) phosphorylation and androgen receptor activation of compound 5n (SGK636) were investigated in LNCaP cells by using Western blot method. Compound 5n (SGK636) was also tested against mRNA expression analysis of the Bax, Bcl-2, Caspase 3, Caspase 9 by using real-time PCR analysis. Compound 5n was given to nude male mice with cancer in comparison to the control group. Compound 5n was found to reverse the malignant phenotype in the nude male mice, whereas the prostate cancer progressed in the control group. Analysis of some blood parameters in the study showed that they were within the normal values with respect to the control. The blood values of the animals treated according to the control group also exhibited compliance with the blood limit values. Molecular docking and dynamics simulation of compound 5n binding to Methionine Aminopeptidase 2 (MetAP2) enzyme rationalized its potential activity. In addition, inhibition assay MetAP2 enzyme of compound 5n was evaluated. Taken together, we suggest compound 5n to be a potential candidate for prostate cancer therapy. © 2020 Elsevier Masson SASen_US
dc.description.sponsorshipUniversität Heidelberg Türkiye Bilimsel ve Teknolojik Araştirma Kurumu, TÜBITAK: 215S009, 315S048en_US
dc.description.sponsorshipThis work was supported by The Scientific and Technical Research Council of Turkey (TÜBİTAK) , Research Fund Project Number: 215S009 (for synthesis, anticancer activity, molecular modeling) and 315S048 (for in vivo procedure). The authors are grateful to Jürgen Gross from the Institute of Organic Chemistry, University of Heidelberg, for his generous help in obtaining HR-MS mass spectra of the synthesized compounds.en_US
dc.description.sponsorshipThis work was supported by The Scientific and Technical Research Council of Turkey (T?B?TAK), Research Fund Project Number: 215S009 (for synthesis, anticancer activity, molecular modeling) and 315S048 (for in vivo procedure). The authors are grateful to J?rgen Gross from the Institute of Organic Chemistry, University of Heidelberg, for his generous help in obtaining HR-MS mass spectra of the synthesized compounds. The experimental protocol was approved by the Local Animal Ethical Committee of Ege University (Approval No. E.U.2016?092). The starting compound, (+) (S)-Naproxen, was obtained from Deva ?la? San. Tic. A. ?. The optical rotation angle experiment was done in Onko-Ko?sel ?la?.en_US
dc.identifier.doi10.1016/j.ejmech.2020.112841
dc.identifier.issn0223-5234
dc.identifier.pmid32998089
dc.identifier.scopus2-s2.0-85091660669
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1016/j.ejmech.2020.112841
dc.identifier.urihttps://hdl.handle.net/20.500.12939/1030
dc.identifier.volume208en_US
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorBirgül, Kaan
dc.language.isoen
dc.publisherElsevier Masson s.r.l.en_US
dc.relation.ispartofEuropean Journal of Medicinal Chemistry
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subject(S)-Naproxenen_US
dc.subjectIVISen_US
dc.subjectLNCaPen_US
dc.subjectMethionine Aminopeptidase-IIen_US
dc.subjectProstate Canceren_US
dc.subjectThioetheren_US
dc.titleSynthesis, molecular modeling, in vivo study and anticancer activity against prostate cancer of (+) (S)-naproxen derivatives
dc.typeArticle

Dosyalar

Koleksiyon

Scopus İndeksli Yayınlar Koleksiyonu
Eczacılık Fakültesi Yayın Koleksiyonu
PubMed İndeksli Yayınlar Koleksiyonu