Anticancer activity and cellular repression of c-MYC by the G-quadruplex-stabilizing 11-piperazinylquindoline is not dependent on direct targeting of the G-quadruplex in the c-MYC promoter.
Anticancer activity and cellular repression of c-MYC by the G-quadruplex-stabilizing 11-piperazinylquindoline is not dependent on direct targeting of the G-quadruplex in the c-MYC promoter.
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DOI：
10.1021/jm300282c
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发表时间：
2012-07-12
影响因子：
7.3
通讯作者：
Hurley, Laurence H.
中科院分区：
文献类型：
--
作者：
Boddupally, Peda V. L.;Hahn, Seongmin;Beman, Cristina;De, Biswanath;Brooks, Tracy A.;Gokhale, Vijay;Hurley, Laurence H.
c-MYC启动子的这个富含g的区域已被证明形成g四重结构，作为c-MYC转录控制的沉默元件。在本研究中，我们合成了一系列11-取代喹啉类似物作为c-MYC g -四聚物的稳定化合物，并对这些化合物的游离活性和体外活性进行了评价。两个先导化合物（4和12）表现出良好的无细胞谱，化合物4 （2-（4-（10h -吲哚[3,2-b]喹啉-11-基）哌嗪-1-基）- n， n-二甲基乙胺）显著下调c-MYC表达。然而，尽管这些化合物具有良好的无细胞活性和对c-MYC基因表达的影响，我们已经证明，使用伯基特淋巴瘤细胞系（ca46特异性）的细胞测定，这些影响不是通过靶向c-MYC g -四重体介导的。因此，在将降低c-MYC的g -四重体相互作用化合物的作用指定为直接靶向这些启动子元件时应谨慎使用，除非该试验或类似的试验证明直接靶向细胞中的g -四重体。
This G-rich region of the c-MYC promoter has been shown to form a G-quadruplex structure, acting as a silencer element for c-MYC transcriptional control. In the present work, we have synthesized a series of 11-substituted quindoline analogs as c-MYC G-quadruplex–stabilizing compounds, and the cell-free and in vitro activity of these compounds were evaluated. Two lead compounds (4 and 12) demonstrated good cell-free profiles, and compound 4 (2-(4-(10H-indolo[3,2-b]quinolin-11-yl)piperazin-1-yl)-N,N-dimethylethanamine) significantly downregulated c-MYC expression. However, despite the good cell-free activity and the effect of these compounds on c-MYC gene expression, we have demonstrated, using a cellular assay in a Burkitt’s lymphoma cell line (CA46-specific), that these effects were not mediated through targeting the c-MYC G-quadruplex. Thus, caution should be used in assigning the effects of G-quadruplex-interactive compounds that lower c-MYC to direct targeting of these promoter elements unless this assay, or similar ones, demonstrates direct targeting of the G-quadruplex in cells.
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影响因子：
10.4
作者：
MOSSMAN, BT
通讯作者：
MOSSMAN, BT
影响因子：
15
作者：
Seenisamy, J;Rezler, EM;Hurley, LH
通讯作者：
Hurley, LH
双芳基双烯酮衍生物：c-myc G-四链体 DNA 的新型选择性配体
影响因子：
3.5
作者：
Peng, Dan;Tan, Jia-Heng;Huang, Zhi-Shu
通讯作者：
Huang, Zhi-Shu
影响因子：
3.9
作者：
Chan, Daniel Shiu-Hin;Yang, Hui;Ma, Dik-Lung
通讯作者：
Ma, Dik-Lung
影响因子：
56.9
作者：
SLAMON, DJ;DEKERNION, JB;CLINE, MJ
通讯作者：
CLINE, MJ