Design, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis

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dc.authoridGumus, Mehmet -- 0000-0001-9262-7940en_US
dc.contributor.authorGumus, Mehmet
dc.contributor.authorOzgur, Aykut
dc.contributor.authorTutar, Lutfi
dc.contributor.authorDisli, Ali
dc.contributor.authorKoca, Irfan
dc.contributor.authorTutar, Yusuf
dc.date.accessioned2019-07-27T12:10:23Z
dc.date.accessioned2019-07-28T09:46:24Z
dc.date.available2019-07-27T12:10:23Z
dc.date.available2019-07-28T09:46:24Z
dc.date.issued2016
dc.department[Gumus, Mehmet -- Koca, Irfan] Bozok Univ, Fac Arts & Sci, Dept Chem, Yozgat, Turkey -- [Ozgur, Aykut -- Tutar, Yusuf] Cumhuriyet Univ, Div Biochem, Dept Basic Sci, Fac Pharm, Sivas, Turkey -- [Tutar, Lutfi] Ahi Evran Univ, Fac Arts & Sci, Dept Mol Biol & Genet, Kirsehir, Turkey -- [Disli, Ali] Gazi Univ, Fac Arts & Sci, Dept Chem, Ankara, Turkeyen_US
dc.description.abstractBackground: Despite development of novel cancer drugs, invasive ductal breast carcinoma and its metastasis are still highly morbid. Therefore, new therapeutic approaches are being developed and Hsp90 is an important target for drug design. For this purpose, a series of benzodiazepine derivatives were designed and synthesized as novel Hsp90 inhibitor. Methods: Benzodiazepine derivatives anticancer activities were determined by XTT cell proliferation assay against human breast cancer cell line (MCF-7). Effects of the compounds on endothelial function were monitored on human vascular endothelium (HUVEC) cell line as well. In order to determine the anti-proliferative mechanism of the compounds, in silico molecular docking studies were performed between Hsp90 ATPase domain and the benzodiazepine derivatives. Further, these compounds perturbation on Hsp90 ATPase function were tested. Fluorescence binding experiments showed that the derivatives bind Hsp90 effectively. Expression analysis of known cancer drug target genes by PCR array experiments suggest that the benzodiazepine derivatives have remarkable anticancer activity. Results: A representative Benzodiazepine derivative D5 binds Hsp90 with Kd value of 3,93 mu M and with estimated free energy of binding -7.99 (kcal/mol). The compound decreases Hsp90 ATPase function and inhibit Hsp90 client protein folding activity. The compound inhibits expression of both Hsp90 isoforms and key proteins (cell cycle receptors; PLK2 and TERT, kinases; PI3KC3 and PRKCE, and growth factors; IGF1, IGF2, KDR, and PDGFRA) on oncogenic pathways. Conclusion: Benzodiazepine derivatives presented here display anticancer activity. The compounds effect on both breast cancer and endothelial cell lines show their potential as drug templates to inhibit breast cancer and its metastasis.en_US
dc.description.sponsorshipTUBITAK (The Scientific and Technological Research Council of Turkey) grant [114Z365]; seed grant from Bozok Universityen_US
dc.description.sponsorshipThis work was funded through TUBITAK (The Scientific and Technological Research Council of Turkey) grant (#114Z365) and a seed grant from Bozok University.en_US
dc.identifier.doi10.2174/1389201017666161031105815en_US
dc.identifier.endpage1245en_US
dc.identifier.issn1389-2010
dc.identifier.issn1873-4316
dc.identifier.issue14en_US
dc.identifier.pmid27804852en_US
dc.identifier.scopus2-s2.0-84995969774en_US
dc.identifier.scopusqualityQ2
dc.identifier.startpage1231en_US
dc.identifier.urihttps://dx.doi.org/10.2174/1389201017666161031105815
dc.identifier.urihttps://hdl.handle.net/20.500.12418/7516
dc.identifier.volume17en_US
dc.identifier.wosWOS:000388513800005en_US
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherBENTHAM SCIENCE PUBL LTDen_US
dc.relation.ispartofCURRENT PHARMACEUTICAL BIOTECHNOLOGYen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectBenzodiazepineen_US
dc.subjectcanceren_US
dc.subjectbone canceren_US
dc.subjectHsp90en_US
dc.subjectclient proteinsen_US
dc.titleDesign, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasisen_US
dc.typeArticleen_US

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