英语翻译Results and DiscussionWe had envisioned the primary benz

英语翻译
Results and Discussion
We had envisioned the primary benzamide and indol-4-one
carbonyl groups as key structural features of this scaffold that
confer tight binding into the ATPase pocket of Hsp90,as
described above.This hypothesis was quickly validated by our
preliminary SARexplorations.Partial or total loss of binding
affinity to Hsp90 occurred when the primary benzamide was
replaced with amides with N-substitutions,a carboxylic acid
or its esters,imidamide,hydroxy imidamide,or its precursor
benzonitrile.Similar results were observed when the carbonyl
of the indol-4-one was converted into an oxime or other
moieties.30 Our follow-on strategy retained these structural
functionalities and focused optimization on the remaining
features around the scaffold.
One of our early strategies was to examine the impact of
side chains attached to the amido benzene ring of the scaffold
on Hsp90 binding affinity and cellular client protein degradation.
We had expected such attachments might enhance
potencies because they would occupy the same space of
enzyme pocket utilized by side chains ofPUseries of inhibitors
as well as rings of 17-AAG (2) and radicicol (5).Our results
indicated there were indeed significant effects on binding
affinities,and they were highly dependent on the positions
of substitutions and the nature of the linker atoms.In general,
the C-3 (meta) substitutions on the benzene frequently led
to lower Hsp90 affinity,erratic SAR,or occasional binding
to off-target proteins that we did not fully characterize (data
not shown).The often reduced and erratic Hsp90 affinity
is believed to be due to steric interference with the Leu 107
residue of Hsp90,which is displaced,on ligand binding,to a
location proximal to the C-3 position.An additional point of
note is that the magnitude of the displacement of Leu 107 is
larger relative to thePU24FCl (7) andCNF-2024 (8) classesof
inhibitors due to the bulky gem-dimethyl group attached to
the indol-4-one moiety.

结果与讨论
我们曾设想主要苯甲酰胺和indol-4-one
羰基作为主要结构特点该支架
赋予紧密结合到酶口袋90,为
以上描述.这个假说很快证实我们的
初步sarexplorations.部分或全部损失的结合
亲和90发生时,苯甲酰胺是小学
取代酰胺与n-substitutions,羧酸
或其酯,imidamide,羟基imidamide,或其前体
腈.类似的结果,观察时,羰基
该indol-4-one转换成肟或其他
我们的后续战略moieties.30保留这些结构
功能和集中优化的剩余
在脚手架的特点.
我们的一个早期的战略审查的影响
附侧链氨基苯环的脚手架
在90的结合亲和力和手机客户端的蛋白质降解.
我们预期这些附件可能会提高
效力,因为他们会占据同一个空间
利用酶口袋侧链ofpuseries抑制剂
以及环（2）17 - AAG和根赤壳菌素（5）.我们的结果
表明确实有显着影响的结合
亲缘关系,它们是高度依赖于位置
替换的性质和连接的原子.一般,
C - 3（元）替代苯频繁
降低90亲和力,不稳定,或偶尔结合
目标蛋白质,我们没有充分的特点（数据
未显示）.往往减少和不稳定的HSP 90的亲和力
被认为是由于空间位阻干扰与107列伊
残留的90,是流离失所,配体结合,以
位置近端的C - 3位.另外一个观点
值得注意的是,位移大小,亮氨酸107
较大的相对thepu24fcl（7）andcnf-2024（8）类
抑制剂由于笨重的gem-dimethyl相连
该indol-4-one基团.