title: Synthesis, Biological Evaluation, and Autophagy Mechanism of 12N-Substituted Sophoridinamines as Novel Anticancer Agents.
abstract: 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 theN'-end could greatly enhance antiproliferation potency. Among them, compound6bpossessing aN'-trimethoxyphenyl methylene exhibited potent antiproliferation effect against three human tumor cell lines including HepG2, leukemia (K562), and breast cancer (HMLE), with IC50between 0.55 and 1.7 μM. The underlying mechanism of6bagainst tumor cells is to block autophagic flux, mainly through neutralizing lysosomal acidity. Our results indicated that compound6bis a potent lysosomal deacidification agent and is accordingly able to block autophagic flux and inhibit tumor cell growth.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
authors.forename: Chongwen
authors.initials: C
authors.lastname: Bi
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ye
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
authors.forename: Yanxiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
authors.forename: Tianyun
authors.initials: T
authors.lastname: Fan
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
authors.forename: Rongguang
authors.initials: R
authors.lastname: Shao
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Deng
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
authors.forename: Danqing
authors.initials: D
authors.lastname: Song
keywords: Sophoridinamine; anticancer; autophagy; lysosomes; structure−activity relationship