Synthesis and Biological Evaluation of Cardiac Glycosides for Cancer Therapy by Targeting the DNA Damage Response.
Synthesis and Biological Evaluation of Cardiac Glycosides for Cancer Therapy by Targeting the DNA Damage Response.
复制标题
DOI：
10.1002/cmdc.202200415
复制
发表时间：
2022-11-04
期刊：
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
强心苷（CGs）是最初用于治疗心脏病的生物活性化合物，但最近的研究表明它们具有抗癌活性。我们之前证明了见血封喉2（AT2）通过影响DNA损伤反应（DDR）通路在KRAS突变的肺癌中具有抗癌活性。为了开发这类分子用于癌症治疗，在此我们报告了一种多步骤的合成路线，利用毒毛旋花子苷K作为起始构建模块来确定构效关系（SARs）。应用了一种系统的结构设计方法，包括对糖部分、糖苷连接体、立体化学和内酯环取代进行修饰，以生成一个O -糖苷和MeON -新糖苷衍生物库。对这些分子的抗癌活性及其对KRAS突变肺癌细胞中DDR信号传导的影响进行了筛选。这些结果证明了化学合成强心苷衍生物的能力，并确定了构效关系以优化AT2作为一种癌症治疗药物。
具有心脏作用的抗癌化合物：这篇论文报道了见血封喉2（强心苷）衍生物的合成。对这些类似物在DNA损伤反应信号传导中的生物学评估表明，通过调整关键的结构部分可以增强它们的活性。
Cardiac glycosides (CGs) are bioactive compounds originally used to treat heart diseases, but recent studies have demonstrated their anticancer activity. We previously demonstrated that Antiaris toxicaria 2 (AT2) possesses anticancer activity in KRAS mutated lung cancers via impinging on the DNA damage response (DDR) pathway. Toward developing this class of molecules for cancer therapy, herein we report a multistep synthetic route utilizing k‐strophanthidin as the initial building block for determination of structure–activity relationships (SARs). A systematic structural design approach was applied that included modifications of the sugar moiety, the glycoside linker, stereochemistry, and lactone ring substitutions to generate a library of O‐glycosides and MeON‐neoglycosides derivatives. These molecules were screened for their anticancer activities and their impact on DDR signaling in KRAS mutant lung cancer cells. These results demonstrate the ability to chemically synthesize CG derivatives and define the SARs to optimize AT2 as a cancer therapeutic. Anticancer compounds with heart: This manuscript reports the synthesis of derivatives of Antiaris toxicaria 2 (cardiac glycosides). Biological evaluation of these analogues in the signalling of the DNA damage response indicate that their activity can be enhanced by tuning key structural moieties.
登录
查看更多内容
影响因子：
11.2
作者：
Raynal NJ;Lee JT;Wang Y;Beaudry A;Madireddi P;Garriga J;Malouf GG;Dumont S;Dettman EJ;Gharibyan V;Ahmed S;Chung W;Childers WE;Abou-Gharbia M;Henry RA;Andrews AJ;Jelinek J;Cui Y;Baylin SB;Gill DL;Issa JP
通讯作者：
Issa JP
影响因子：
14.9
作者：
Gavande NS;VanderVere-Carozza PS;Pawelczak KS;Mendoza-Munoz P;Vernon TL;Hanakahi LA;Summerlin M;Dynlacht JR;Farmer AH;Sears CR;Nasrallah NA;Garrett J;Turchi JJ
通讯作者：
Turchi JJ
影响因子：
0.7
作者：
Bajaj, Sumit O.;Farnsworth, Jamison R.;O'Doherty, George A.
通讯作者：
O'Doherty, George A.
影响因子：
4.2
作者：
Wang, Hua-Yu Leo;Rojanasakul, Yon;O'Doherty, George A.
通讯作者：
O'Doherty, George A.
影响因子：
14.5
作者：
Wang, Fangfang;Jin, Sora;Pozo, Franklin Mayca;Tian, Danmei;Tang, Xiyang;Dai, Yi;Yao, Xinsheng;Tang, Jinshan;Zhang, Youwei
通讯作者：
Zhang, Youwei