A synthetic manassantin a derivative inhibits hypoxia-inducible factor 1 and tumor growth.

Abstract

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-1α 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.

• Authors: Liwei Lang, Xiaoyu Liu, Yan Li, Qing Zhou, Ping Xie, Chunhong Yan, Xiaoguang Chen
• Journal: PloS one (PLoS One) Vol. 9 Issue 6 Pg. e99584 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24925080 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Lignans
• manassantin A
• Paclitaxel

Topics

• Animals
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Hypoxia (drug effects)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Lignans (chemistry, pharmacology)
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms (genetics, pathology)
• Paclitaxel (pharmacology)
• Transcription, Genetic (drug effects)
• Xenograft Model Antitumor Assays