Design Synthesis and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis
Yazarlar (6)
Mehmet Gümüş
Bozok Üniversitesi, Türkiye
Aykut Özgür
Cumhuriyet Üniversitesi, Türkiye
Dr. Öğr. Üyesi Lütfi TUTAR
Kırşehir Ahi Evran Üniversitesi, Türkiye
Ali Dişli
Gazi Üniversitesi, Türkiye
İrfan Koca
Bozok Üniversitesi, Türkiye
Yusuf Tutar
Cumhuriyet Üniversitesi, Türkiye
| Makale Türü | Özgün Makale (SSCI, AHCI, SCI, SCI-Exp dergilerinde yayınlanan tam makale) | ||
| Dergi Adı | Current Pharmaceutical Biotechnology | ||
| Dergi ISSN | 1389-2010 Wos Dergi Scopus Dergi | ||
| Dergi Tarandığı Indeksler | SCI-Expanded | ||
| Makale Dili | İngilizce | Basım Tarihi | 11-2016 |
| Cilt / Sayı / Sayfa | 17 / 14 / 1231–1245 | DOI | 10.2174/1389201017666161031105815 |
| Makale Linki | http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1389-2010&volume=17&issue=14&spage=1231 | ||
| Özet |
| Background: 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. |
| Anahtar Kelimeler |
| Benzodiazepine, cancer, bone cancer, Hsp90, client proteins |
BM Sürdürülebilir Kalkınma Amaçları
| Atıf Sayıları | |
| WoS | 21 |
| SCOPUS | 23 |
| Google Scholar | 33 |