
International Journal of Peptide Research and Therapeutics p. 1361 - 1367 (2019)
Update date:2022-08-31
Topics:
Li, Songtao
Zhao, Hongling
Wang, Ruxing
Wang, Jianping
Mao, Xiaoxia
Hao, Ting
Chang, Xiaomin
Zhao, Enhong
Yin, Zhifeng
Deng, Shuhua
Yang, Yaqi
Wang, Huina
It is demonstrated that gonadotropin-releasing hormone (GnRH) analogs can directly inhibit the proliferation of reproductive tissue cancer cells, but the poor pharmacokinetic properties still restrict their application in treating hormone-dependent diseases. Modifications in position 6 and 10 of natural GnRH can improve the metabolic stability. In order to study the effect of incorporation Cys6 substitution with C-terminal Pro9-NHEt modification and dimerization of linear peptides on metabolic stability and antiproliferative activity of GnRH analogs, two new GnRH analogs [l-Cys6, desGly10, Pro9-NHEt]-GnRH (1) and [d-Cys6, desGly10, Pro9-NHEt]-GnRH (2), and their corresponding dimer derivatives ([l-Cys6, desGly10, Pro9-NHEt]-GnRH)2 (3) and ([d-Cys6, desGly10, Pro9-NHEt]-GnRH)2 (4) were synthesized. Incubation of these analogs with human serum was carried out to evaluate their metabolic stability, and direct growth inhibitory effect of the two dimer derivatives 3 and 4 on MCF-7 human breast cancer cell line was examined by MTT assay. The metabolic stability of dimer derivatives 3 and 4 was remarkably improved in comparison with natural GnRH. The d-Cys6 substituted dimer derivative 4 exhibited higher inhibitory effect (29.6–39.7% growth reduction) on cell growth than its corresponding counterpart 3 (21.8–26.2% growth reduction) at concentration range of 50, 100 and 200 μΜ. The cell growth inhibition of leuprolide was 16.4–27.2% at the tested concentrations. The dimer derivative 4 was the most stable and active GnRH analog in this study and has the potential for future preclinical investigations as promising antitumor drug candidate.
View More
Contact:+86 512 6287 2180
Address:398 Ruoshui Road, Suzhou Industrial Park, Suzhou, Jiangsu, P. R. China
Yuan Shi(SuQian)Biotechnology Co.,Ltd
website:http://www.yuanshibio.com
Contact:+86-527-84226672
Address:jiangsu suqian
Liaoning Yufeng Chemical Co.,Ltd.
Contact:86-0419-3418888
Address:The metallurgical industrial zone,shoushan town, Liaoyang, Liaoning, China
Frapp's Chemical (NFTZ) Co.,Ltd
Contact:+86-576-86137892
Address:General Chamber of Commercial Building, 159 Wanchang Middle Road, Wenling, Zhejiang, China
Contact:+86-371-55981030
Address:Room 1571, Macalline Soho, No.1, Shangdu Road, Zhengzhou, Henan
Doi:10.1021/acs.orglett.6b02571
(2016)Doi:10.1039/jr9340000161
(1934)Doi:10.1039/c8dt03225d
(2018)Doi:10.1246/cl.1992.509
(1992)Doi:10.1111/1468-0262.00113
(1931)Doi:10.3390/ijms19102994
(2018)