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Strategic Incorporation of Fluorine into Taxoid Anticancer Agents for Medicinal Chemistry and Chemical Biology Studies.
Journal of Fluorine Chemistry ( IF 1.9 ) Pub Date : 2017-08-22 , DOI: 10.1016/j.jfluchem.2016.12.016
Iwao Ojima 1, 2
Affiliation  

This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to taxoid anticancer agents and their tumor-targeted drug delivery systems (TTDDSs) for medicinal chemistry and chemical biology studies. Novel 3'-difluorovinyltaxoids were strategically designed to block the metabolism by cytochrome P-450, synthesized, and evaluated for their cytotoxicity against drug-sensitive and multidrug-resistant (MDR) human cancer cell lines. 3'-Difluorovinyltaxoids exhibited impressive activities against these cancer cell lines. More significantly, a representative 3'-difluorovinyltaxoid exhibited 230-33,000 times higher potency than conventional anticancer drugs against cancer stem cell-enriched HCT-116 cell line. Studies on the mechanism of action (MOA) of these fluorotaxoids were performed by tubulin polymerization assay, morphology analysis by electron microscopy (EM) and protein binding assays. Novel 19F NMR probes, BLT-F2 and BLT-S-F6, were designed by strategically incorporating fluorine, CF3 and CF3O groups into tumor-targeting drug conjugates. These 19F-probes were designed and synthesized to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time 19F NMR analysis. Time-resolved 19F NMR study on probe BLT-F2 revealed a stepwise mechanism for the release of a fluorotaxoid, which might not be detected by other analytical methods. Probe BLT-S-F6 were very useful to study the stability and reactivity of the drug delivery system in human blood plasma by 19F NMR. The clean analysis of the linker stability and reactivity of drug conjugates in blood plasma by HPLC and 1H NMR is very challenging, but the use of 19F NMR and suitable 19F probes can provide a practical solution to this problem.

中文翻译:

战略性地将氟掺入紫杉类抗癌药中,用于药物化学和化学生物学研究。

该说明例证了我们最近在将氟和有机氟基团战略性纳入紫杉类抗癌药及其针对肿瘤的药物递送系统(TTDDSs)进行药物化学和化学生物学研究的最新进展。新型3'-二氟乙烯基紫杉醇经过战略性设计,可通过细胞色素P-450阻断新陈代谢,并进行合成并评估其对药物敏感性和耐多药(MDR)人类癌细胞系的细胞毒性。3'-二氟乙烯基紫杉醇对这些癌细胞系表现出令人印象深刻的活性。更重要的是,具有代表性的3'-二氟乙烯基紫杉醇对富含癌症干细胞的HCT-116细胞系的效能比传统的抗癌药物高230-33,000倍。通过微管蛋白聚合测定,电子显微镜(EM)的形态分析和蛋白质结合测定,对这些氟类化合物的作用机理(MOA)进行了研究。新型19F NMR探针BLT-F2和BLT-S-F6是通过将氟,CF3和CF3O基团策略性地掺入靶向肿瘤的药物偶联物中而设计的。设计并合成了这些19F探针,以通过实时19F NMR分析研究接头裂解的机理以及影响其血浆和代谢稳定性的因素。在探针BLT-F2上进行的时间分辨19 F NMR研究表明,氟代类固醇释放的逐步机理,可能无法通过其他分析方法检测到。探针BLT-S-F6对于通过19F NMR研究药物在人体血浆中的稳定性和反应性非常有用。
更新日期:2017-01-03
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