维吉尼亚霉素
奎努普瑞汀
化学
达尔福普列斯汀
核糖体
细胞生长
干细胞
生物化学
细胞生物学
抗生素
生物
核糖核酸
遗传学
金黄色葡萄球菌
万古霉素
细菌
基因
作者
Denise Sighel,Giulia Battistini,Emanuele Filiberto Rosatti,Jacopo Vigna,Matteo Pavan,Romina Belli,Daniele Peroni,Federica Alessandrini,Sara Longhi,Michael Pancher,Joanna Rorbach,Stefano Moro,Alessandro Quattrone,Ines Mancini
标识
DOI:10.1016/j.ejmech.2022.114979
摘要
New therapeutic strategies for glioblastoma treatment, especially tackling the tumour's glioblastoma stem cell (GSC) component, are an urgent medical need. Recently, mitochondrial translation inhibition has been shown to affect GSC growth, clonogenicity, and self-renewal capability, therefore becoming an attractive therapeutic target. The combination of streptogramins B and A antibiotics quinupristin/dalfopristin (Q/D), which inhibits mitochondrial ribosome function, affects GSCs more effectively in vitro than the standard of care temozolomide. Here, docking calculations based on the cryo-EM structure of the Q/D-bound mitochondrial ribosome have been used to develop a series of streptogramin A derivatives. We obtained twenty-two new and known molecules starting from the dalfopristin and virginiamycin M1 scaffolds. A structure-activity relationship refinement was performed to evaluate the capability of these compounds to suppress GSC growth and inhibit mitochondrial translation, either alone or in combination with quinupristin. Finally, quantitative ultra HPLC-mass spectrometry allowed us to assess the cell penetration of some of these derivatives. Among all, the fluorine derivatives of dalfopristin and virginiamycin M1, (16R)-1e and (16R)-2e, respectively, and flopristin resulted in being more potent than the corresponding lead compounds and penetrating to a greater extent into the cells. We, therefore, propose these three compounds for further evaluation in vivo as antineoplastic agents.
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