Structure-activity relationship studies of salinosporamide a (NPI-0052), a novel marine derived proteasome inhibitor

被引：200
作者：
Macherla, VR
Mitchell, SS
Manam, RR
Reed, KA
Chao, TH
Nicholson, B
Deyanat-Yazdi, G
Mai, B
Jensen, PR
Fenical, WF
Neuteboom, STC
Lam, KS
Palladino, MA
Potts, BCM
机构：
[1] Nereus Pharmaceut Inc, San Diego, CA 92121 USA
[2] Univ Calif San Diego, Scripps Inst Oceanog, Ctr Marine Biotechnol & Biomed, La Jolla, CA 92093 USA
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 11期
关键词：
D O I：
10.1021/jm048995+
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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.
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收藏
页码：3684 / 3687
页数：4
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