(1S,2E,4S,7E,11E)-2,7,11-Cembratriene-4,6-diol semisynthetic analogs as novel c-Met inhibitors for the control of c-Met-dependent breast malignancies.
(1S,2E,4S,7E,11E)-2,7,11-Cembratriene-4,6-diol semisynthetic analogs as novel c-Met inhibitors for the control of c-Met-dependent breast malignancies.
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（1s，2e，4s，7e，11e）-2,7,11-螺旋三烯-4,6-二醇半合成类似物，作为用于控制C-Met依赖性乳腺癌的新型C-MET抑制剂。
DOI：
10.1016/j.bmc.2016.09.032
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发表时间：
2016-11-15
影响因子：
3.5
通讯作者：
El Sayed KA
中科院分区：
文献类型：
--
作者：
Ebrahim HY;Mohyeldin MM;Hailat MM;El Sayed KA
（1S,2E,4S,6R,7E,11E）-2,7,11-烯-4,6-二醇(1)及其4-表类似物(2)是大多数烟草物种中几种关键风味成分的类膜前体。在商业烟草发酵过程中，有近40-60%的1和2被有意降解。然而，1和2显示出有希望的生物活性，包括抗癌。乳腺癌是女性中诊断最多的癌症，也是第二大女性疾病杀手。酪氨酸激酶c-Met受体与某些乳腺癌表型的侵袭性相关，因此被认为是有效的治疗靶点。本研究报道了利用结构和配体相结合的方法，发现并优化了烟草类膜1作为一种新的c-Met抑制支架。1在中等μM浓度下对c-Met过表达的MDA-MB-231乳腺癌细胞表现出抗增殖、抗迁移和抗侵袭作用。Z ' -LYTE激酶平台和Western blot分析发现c-Met是一个潜在的大分子靶点。提出合理设计氨基甲酸酯类似物，以探测额外的靶向c-Met相互作用并提高细胞效力。6-苯基氨基甲酸酯3具有增强的c-Met抑制活性。研究了3′苯基上不同取代基的构效关系。活性最高的类似物20在低μM浓度下对MDA-MB-231乳腺癌细胞具有较强的体外抗癌活性，对非致瘤性MCF-10A乳腺上皮细胞的毒性最小。在Z ' -LYTE激酶检测和多种细胞c-Met驱动信号通路中，类Cembranoid 20能有效抑制c-Met的催化活性。此外，20在乳腺癌异种移植胸腺小鼠模型中显示出强大的抗肿瘤活性，因此被提升到领先水平。类cembranoid是一种新型的c-Met抑制剂，适用于未来用于控制c-Met依赖性恶性肿瘤。
(1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (1) and its 4-epi-analog (2) are the cembranoid precursors to several key flavor ingredients in most Nicotiana (tobacco) species. Nearly 40–60% of 1 and 2 are purposely degraded during the commercial tobacco fermentation. However, 1 and 2 display promising bioactivities, including anticancer. Breast cancer is the most diagnosed cancer in women and ranked second female disease killer. The receptor tyrosine kinase c-Met correlates with aggressiveness of certain breast cancer phenotypes and thus considered a valid therapeutic target. This study reports the discovery and optimization of the tobacco-based cembranoid 1 as a novel c-Met inhibitory scaffold using combined structure- and ligand-based approaches. 1 displayed antiproliferative, anti-migratory and anti-invasive effects against the c-Met overexpressing MDA-MB-231 breast cancer cells at moderate μM concentrations. The Z′-LYTE kinase platform and Western blot analysis identified c-Met as a potential macromolecular target. Rationally designed carbamate analogs were proposed to probe additional targeted c-Met interactions and improve the cellular potency. The 6-phenyl carbamate 3 showed enhanced c-Met inhibitory activity. Structure-activity relationships of different substituents on the 3’s phenyl moiety were studied. The most active analog 20 showed potent in vitro anticancer activities against the MDA-MB-231 breast cancer cells at low μM concentrations, with minimal toxicity on the non-tumorigenic MCF-10A mammary epithelial cells. Cembranoid 20 potently inhibited the c-Met catalytic activity in Z′-LYTE kinase assay and various cellular c-Met-driven signaling pathways. Furthermore, 20 displayed a robust antitumor activity in a breast cancer xenograft athymic mouse model and thus promoted to the lead rank. Cembranoids are novel c-Met inhibitors appropriate for future use to control c-Met dependent malignancies.
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影响因子：
3.7
作者：
Akl MR;Ayoub NM;Mohyeldin MM;Busnena BA;Foudah AI;Liu YY;Sayed KA
通讯作者：
Sayed KA
影响因子：
1.7
作者：
Lee, Joo Yun;Lee, Kwangho;Chae, Chong Hak
通讯作者：
Chae, Chong Hak
影响因子：
5
作者：
Leong, Anthony S. -Y.;Zhuang, Zhengping
通讯作者：
Zhuang, Zhengping
影响因子：
3.5
作者：
Caballero, Julio;Quiliano, Miguel;Deharo, Eric
通讯作者：
Deharo, Eric
影响因子：
6.2
作者：
Ocal, IT;Dolled-Filhart, M;Rimm, DL
通讯作者：
Rimm, DL