Identification and biological evaluation of novel benzothiazole derivatives bearing a pyridine-semicarbazone moiety as apoptosis inducers via activation of procaspase-3 to caspase-3
Identification and biological evaluation of novel benzothiazole derivatives bearing a pyridine-semicarbazone moiety as apoptosis inducers via activation of procaspase-3 to caspase-3
复制标题
通过将 procaspase-3 激活为 caspase-3 来鉴定和生物学评价带有吡啶-缩氨基脲部分的新型苯并噻唑衍生物作为凋亡诱导剂
DOI：
10.1039/c8md00624e
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Wang Cuifang
中科院分区：
文献类型：
--
作者：
Ma Junjie;Ni Xin;Gao Yali;Huang Kun;Liu Jiaan;Wang Yu;Chen Roufen;Wang Cuifang
设计、合成了三个系列的化合物，并评估了它们对半胱天冬酶原-3过表达癌细胞系（U937）和半胱天冬酶原-3非表达癌细胞系（MCF-7）的体外抗癌活性，以排除脱靶效应。生物学评价导致一系列苯并噻唑衍生物轴承吡啶-缩氨基脲部分，8 j和8 k，有前途的抗癌活性和显着的选择性鉴定。进一步的机制研究表明，化合物8 j和8 k可通过激活caspase-3活化caspase-3而诱导癌细胞凋亡，其中化合物8 k的caspase-3活化活性最强。结构-活性关系（SAR）表明，苯并噻唑和N，N，O-供体组的存在对于抗癌活性和选择性是至关重要的，并且降低N，N，O-供体组的电子密度导致抗癌活性和选择性的急剧下降。此外，还进行了体内毒性评价（斑马鱼）和代谢稳定性研究（人、大鼠和小鼠肝微粒体），为进一步的体内PK/PD研究提供可靠的指导。
Three series of compounds were designed, synthesized and evaluated for their in vitro anticancer activity against a procaspase-3 over-expression cancer cell line (U937) and a procaspase-3 no-expression cancer cell line (MCF-7) to rule out off-target effects. Biological evaluation led to the identification of a series of benzothiazole derivatives bearing a pyridine-semicarbazone moiety, 8j and 8k, with promising anticancer activity and remarkable selectivity. Further mechanism studies revealed that compounds 8j and 8k could induce apoptosis of cancer cells by activating procaspase-3 to caspase-3, and compound 8k exhibited the strongest procaspase-3 activation activity. Structure–activity relationships (SARs) revealed that the presence of benzothiazole and an N,N,O-donor set is crucial for the anticancer activity and selectivity, and reducing the electron density of the N,N,O-donor set results in a dramatic decline in the anticancer activity and selectivity. Furthermore, toxicity evaluation (zebrafish) in vivo and metabolic stability studies (human, rat and mouse liver microsomes) were performed to provide reliable guidance for further PK/PD studies in vivo.