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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis and evaluation of ~(18)F-labeled ATP competitive inhibitors of topoisomerase II as probes for imaging topoisomerase II expression
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Synthesis and evaluation of ~(18)F-labeled ATP competitive inhibitors of topoisomerase II as probes for imaging topoisomerase II expression

机译:〜(18)F标记的拓扑异构酶II ATP竞争性抑制剂的合成和评价,作为成像拓扑异构酶II表达的探针

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摘要

Type II topoisomerase (Topo-II) is an ATP-dependent enzyme that is essential in the transcription, replication, and chromosome segregation processes and, as such, represents an attractive target for cancer therapy. Numerous studies indicate that the response to treatment with Topo-II inhibitors is highly dependent on both the levels and the activity of the enzyme. Consequently, a non-invasive assay to measure tumoral Topo-II levels has the potential to differentiate responders from non-responders. With the ultimate goal of developing a radiofluorinated tracer for positron emission tomography (PET) imaging, we have designed, synthesized, and evaluated a set of fluorinated compounds based on the structure of the ATP-competitive Topo-II inhibitor QAP1. Compounds 18 and 19b showed inhibition of Topo-II in in vitro assays and exhibited moderate, Topo-II level dependent cytotoxicity in SK-BR-3 and MCF-7 cell lines. Based on these results, ~(18)F-labeled analogs of these two compounds were synthesized and evaluated as PET probes for imaging Topo-II overexpression in mice bearing SK-BR-3 xenografts. [~(18)F]-18 and [~(18)F]-19b were synthesized from their corresponding protected tosylated derivatives by fluorination and subsequent deprotection. Small animal PET imaging studies indicated that both compounds do not accumulate in tumors and exhibit poor pharmacokinetics, clearing from the blood pool very rapidly and getting metabolized over. The insights gained from the current study will surely aid in the design and construction of future generations of PET agents for the non-invasive delineation of Topo-II expression.
机译:II型拓扑异构酶(Topo-II)是ATP依赖的酶,在转录,复制和染色体分离过程中必不可少,因此,它是癌症治疗的诱人靶标。大量研究表明,Topo-II抑制剂对治疗的反应高度依赖于酶的水平和活性。因此,一种用于测量肿瘤Topo-II水平的非侵入性测定方法有可能区分反应者和非反应者。为了开发用于正电子发射断层扫描(PET)成像的放射性氟化示踪剂的最终目标,我们根据ATP竞争性Topo-II抑制剂QAP1的结构设计,合成和评估了一组氟化化合物。化合物18和19b在体外试验中显示了Topo-II的抑制作用,并在SK-BR-3和MCF-7细胞系中表现出中等的Topo-II水平依赖性细胞毒性。基于这些结果,合成了这两种化合物的〜(18)F标记类似物,并作为PET探针进行了评估,以对携带SK-BR-3异种移植物的小鼠中Topo-II过表达进行成像。 [〜(18)F] -18和[〜(18F)]-19b是通过氟化和随后的脱保护反应,由相应的受保护甲苯磺酸衍生物合成的。小动物PET成像研究表明,这两种化合物均不会在肿瘤中积聚,并且显示出较差的药代动力学,非常快地从血池中清除并代谢。从当前研究中获得的见识必将有助于无创描绘Topo-II表达的PET药物的下一代设计和构建。

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