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【BMC】Development of Radamide Analogs as Grp94 Inhibitors

2014-7-9 17:28| 发布者: Mcdull| 查看: 2624| 评论: 0|原作者: influenza|来自: 捷报频传

摘要: 作为群众作者,发一篇。这篇东东的chemistry几个作者做的都差不多,老板偏向着老美,最后让老美博后写了。都以为能中JMC,结果投了修,修完还是据,最后到了BMC。总体下来biology也做了不少,虽然选择性不是很高,做的 ...


Authors: Aaron Muth, Vincent Crowley, Anuj Khandelwal, Sanket Mishra, Jinbo Zhao, Jessica Hall, Brian S.J. Blagg

Journal: Bioorg. Med. Chem.

http://www.sciencedirect.com/sci ... i/S0968089614004519

GA:

Abstract
Hsp90 isoform-selective inhibition is highly desired as it can potentially avoid the toxic side-effects of pan-inhibition. The current study developed selective inhibitors of one such isoform, Grp94, predicated on the chimeric and pan-Hsp90 inhibitor, radamide (RDA). Replacement of the quinone moiety of RDA with a phenyl ring (2) was found to be better suited for Grp94 inhibition as it can fully interact with a unique hydrophobic pocket present in Grp94. An extensive SAR for this scaffold showed that substitutions at the 2- and 4-positions (8 and 27, respectively) manifested excellent Grp94 affinity and selectivity. Introduction of heteroatoms into the ring also proved beneficial, with a 2-pyridine derivative (38) exhibiting the highest Grp94 affinity (Kd = 820 nM). Subsequent cell-based assays showed that these Grp94 inhibitors inhibit migration of the metastatic breast cancer cell line, MDA-MB-231, as well as exhibit an anti-proliferative affect against the multiple myeloma cell line, RPMI 8226.

1-s2.0-S0968089614004519-fx1.jpg

作为群众作者,发一篇。这篇东东的chemistry几个作者做的都差不多,老板偏向着老美,最后让老美博后写了。都以为能中JMC,结果投了修,修完还是据,最后到了BMC。总体下来biology也做了不少,虽然选择性不是很高,做的还是挺全面的。

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