A Synthetic Manassantin A Derivative Inhibits Hypoxia-Inducible Factor 1 and Tumor Growth

被引：22

作者：

Lang, Liwei ^{[1
,2
,4
]}

Liu, Xiaoyu ^{[2
,3
]}

Li, Yan ^{[1
,2
]}

Zhou, Qing ^{[1
,2
]}

Xie, Ping ^{[2
,3
]}

Yan, Chunhong ^{[4
]}

Chen, Xiaoguang ^{[1
,2
]}

机构：

[1] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Dept Pharmacol, Beijing 100050, Peoples R China

[2] Peking Union Med Coll, Beijing 100021, Peoples R China

[3] Chinese Acad Med Sci, Inst Mat Med, Dept Synthet Med Chem, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China

[4] Georgia Regents Univ, GRU Canc Ctr, Dept Biochem & Mol Biol, Med Coll Georgia, Augusta, GA 30901 USA

来源：

PLOS ONE | 2014年 / 9卷 / 06期

基金：

北京市自然科学基金;

关键词：

SMALL-MOLECULE INHIBITORS; SAURURUS-CHINENSIS; ACTIVATION; RESISTANCE; ARYLATION; LIGNANS; ALPHA;

D O I：

10.1371/journal.pone.0099584

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The dineolignan manassantin A from Saururaceae was recently identified as a hypoxia-inducible factor 1 (HIF-1) inhibitor, but its in-vivo anti-tumor effect has not been explored. We synthesized a series of manassantin A derivatives, and found that replacing the central tetrahydrofuran moiety with a cyclopentane ring yielded a compound (LXY6006) with increased HIF-1-inhibitory activity yet decreased stereochemically complexity amenable to a simplified synthesis scheme. LXY6006 inhibited HIF-1 alpha nuclear accumulation induced by hypoxia, and inhibited cancer cell growth as a consequence of G2/M arrest. Oral administration of LXY6006 significantly inhibited growth of breast, lung, and pancreatic tumors implanted in nude mice. These results indicate that LXY6006 represents a novel class of agents targeting a broad range of human cancers.

引用

页数：9

共 25 条

[1]

Manassantin A and B From Saururus chinensis Inhibit Interleukin-6-Induced Signal Transducer and Activator of Transcription 3 Activation in Hep3B Cells [J].