Structure-activity relationship studies of salinosporamide a (NPI-0052), a novel marine derived proteasome inhibitor
Structure-activity relationship studies of salinosporamide a (NPI-0052), a novel marine derived proteasome inhibitor
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DOI：
10.1021/jm048995
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发表时间：
2005-06-02
影响因子：
7.3
通讯作者：
Potts, BCM
中科院分区：
文献类型：
--
作者：
Macherla, VR;Mitchell, SS;Potts, BCM
Salinosporamide A （1,npi -0052）是一种有效的蛋白酶体抑制剂，正在开发用于治疗癌症。在这项研究中，我们检测了一系列类似物的细胞毒性、蛋白酶体抑制和nf - κ B活化的抑制作用。在以细胞为基础的测定中，随着氯乙基被非卤化取代基取代，效力显著降低。卤素交换和环己烯环环氧化反应耐受性良好，而一些立体化学修饰明显减弱活性。这些发现为这个小说系列中的结构-活性关系提供了见解。
Salinosporamide A (1, NPI-0052) is a potent proteasome inhibitor in development for treating cancer. In this study, a series of analogues was assayed for cytotoxicity, proteasome inhibition, and inhibition of NF-kappa B activation. Marked reductions in potency in cell-based assays accompanied replacement of the chloroethyl group with unhalogenated substituents. Halogen exchange and cyclohexene ring epoxidation were well tolerated, while some stereochemical modifications significantly attenuated activity. These findings provide insights into structure-activity relationships within this novel series.