- Sophoridine Derivatives Induce Apoptosis and Autophagy to Suppress the Growth of Triple-Negative Breast Cancer through Inhibition of mTOR Signaling
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In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were
- Dai, Linlin,Wang, Luyao,Tan, Cheng,Cai, Jun,Shen, Hongsheng,Zhang, Ting,Zhi, Shuang,Yang, Zibo,Hu, Yunhui,Zhao, Xiumei,Li, Dongdong
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- Synthesis, Biological Evaluation, and Autophagy Mechanism of 12N-Substituted Sophoridinamines as Novel Anticancer Agents
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A series of 12N-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure-activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N′-end could greatly enhance antiproliferation potency. Among them, compound 6b possessing a N′-trimethoxyphenyl methylene exhibited potent antiproliferation effect against three human tumor cell lines including HepG2, leukemia (K562), and breast cancer (HMLE), with IC50 between 0.55 and 1.7 μM. The underlying mechanism of 6b against tumor cells is to block autophagic flux, mainly through neutralizing lysosomal acidity. Our results indicated that compound 6b is a potent lysosomal deacidification agent and is accordingly able to block autophagic flux and inhibit tumor cell growth.
- Bi, Chongwen,Zhang, Na,Yang, Peng,Ye, Cheng,Wang, Yanxiang,Fan, Tianyun,Shao, Rongguang,Deng, Hongbin,Song, Danqing
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p. 245 - 250
(2017/03/08)
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- Sophoridine amine derivative, preparation method thereof and application
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The invention relates to a sophoridine amine derivative, a preparation method thereof and an application, in particular to a compound as shown in a formula I, an optical isomer of the compound, a solvate of the compound or pharmaceutically acceptable salt of the compound. The compound is novel in structure and has excellent anti-tumor activity and good inhibitory activity for cancers such as liver cancer, lung adenocarcinoma, breast cancer, stomach cancer, colon cancer, cervical cancer, ovarian cancer, lymphoma, glioma, brain glioma and melanoma.
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- Novel N-substituted sophoridinol derivatives as anticancer agents
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Using sophoridine (1) as the lead compound, a series of new N-substituted sophoridinic acid derivatives were designed, synthesized and evaluated for their cytotoxicity. SAR analysis indicated that introduction of a chlorobenzyl on the 12-nitrogen atom of sophoridinol might significantly enhance the antiproliferative activity. Of the newly synthesized compounds, sophoridinol analogue 9k exhibited a potent effect against six human tumor cell lines (liver, colon, breast, lung, glioma and nasopharyngeal). The mode of action of 9k was to inhibit the DNA topoisomerase I activity, followed by the G0/G1 phase arrest. It also showed a moderate oral bioavailability and good safety in vivo. Therefore, compound 9k has been selected as a novel-scaffold lead for further structural optimizations or as a chemical probe for exploring anticancer pathways of this kinds of compounds.
- Bi, Chong-Wen,Zhang, Cai-Xia,Li, Ying-Hong,Tang, Sheng,Deng, Hong-Bin,Zhao, Wu-Li,Wang, Zhen,Shao, Rong-Guang,Song, Dan-Qing
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