Structure-activity relationship studies on O-alkylamino-tethered salicylamide derivatives with various amino acid linkers as potent anticancer agents.
Structure-activity relationship studies on O-alkylamino-tethered salicylamide derivatives with various amino acid linkers as potent anticancer agents.
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DOI：
10.1016/j.ejmech.2022.114229
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发表时间：
2022-04-15
影响因子：
6.7
通讯作者：
Zhou, Jia
中科院分区：
文献类型：
--
作者：
Xu, Jimin;Kim, Hyejin;Dong, Jiabin;Chen, Haiying;Xu, Junhai;Ma, Ruixia;Zhou, Mingxiang;Wang, Tianzhi;Shen, Qiang;Zhou, Jia
在我们持续的SAR研究中，我们设计、合成了一系列具有不同氨基酸连接物的o-烷基胺系链水杨胺衍生物，并对其进行了生物学评价。五种具有不同代表性化学结构的化合物被发现具有广泛的抗增殖活性，对所有测试的er阳性乳腺癌（BC）和三阴性乳腺癌（TNBC）细胞系有效，具有低微摩尔IC50值。其中，化合物9a （JMX0293）对MDA-MB-231细胞系的IC50值为3.38±0.37 μM，对人非致瘤性乳腺上皮细胞系MCF-10A的IC50值为50 ~ 60 μM，毒性较低。进一步的机制研究表明，化合物9a可抑制TNBC MDA-MB-231细胞STAT3磷酸化，促进细胞凋亡。更重要的是，化合物9a在体内可显著抑制MDA-MB-231异种移植瘤的生长，且无明显毒性，表明其作为一种有前景的抗癌候选药物具有进一步临床开发的潜力。
In our continued SAR study efforts, a series of O-alkylamino-tethered salicylamide derivatives with various amino acid linkers has been designed, synthesized, and biologically evaluated as potent anticancer agents. Five selected compounds with different representative chemical structures were found to show broad anti-proliferative activities, effective against all tested ER-positive breast cancer (BC) and triple-negative breast cancer (TNBC) cell lines with low micromolar IC50 values. Among these compounds, compound 9a (JMX0293) maintained good potency against MDA-MB-231 cell line (IC50 = 3.38 ± 0.37 μM) while exhibiting very low toxicity against human non-tumorigenic breast epithelial cell line MCF-10A (IC50 > 60 μM). Further mechanistic studies showed that compound 9a could inhibit STAT3 phosphorylation and contribute to apoptosis in TNBC MDA-MB-231 cells. More importantly, compound 9a significantly suppressed MDA-MB-231 xenograft tumor growth in vivo without significant toxicity, indicating its great potential as a promising anticancer drug candidate for further clinical development.
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影响因子：
4.8
作者：
Chen W;Mook RA Jr;Premont RT;Wang J
通讯作者：
Wang J
影响因子：
4.2
作者：
Chen, Haijun;Yang, Zhengduo;Ding, Chunyong;Chu, Lili;Zhang, Yusong;Terry, Kristin;Liu, Huiling;Shen, Qiang;Zhou, Jia
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Zhou, Jia
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通讯作者：
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50.3
作者：
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通讯作者：
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影响因子：
15.9
作者：
Bromberg, J
通讯作者：
Bromberg, J