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

Lang, Liwei; Liu, Xiaoyu; Li, Yan; Zhou, Qing; Xie, Ping; Yan, Chunhong; Chen, Xiaoguang

doi:10.1371/journal.pone.0099584

Cited by 19 publications

(15 citation statements)

References 23 publications

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“…Furthermore, more derivatives of manassantin A were reported with improved biological potency and simplified structural complexity . Compound 49 , with a cyclopentane ring instead of the furan ring in compound 43 , contains fewer chiral centers and is easier to synthesize.…”

Section: Manassantin a And Analogsmentioning

confidence: 73%

“…Analog 49 inhibited HIF‐1 activity with an IC 50 value of 4.11 nM, showing higher potency than 43 (IC 50 = 35.2 nM) . Another cyclopentane derivative (50) also exhibited more potent biological activity with an IC 50 value of 0.35 nM compared to the original compound 43 (IC 50 = 52 nM in this experiment) . The less complex analog 51 exhibited good HIF‐1 inhibitory activity in different cancer cell lines with better potency than manassantin A …”

Section: Manassantin a And Analogsmentioning

confidence: 99%

“…51 Furthermore, more derivatives of manassantin A were reported with improved biological potency and simplified structural complexity. 52 53 The less complex analog 51 exhibited good HIF-1 inhibitory activity in different cancer cell lines with better potency than manassantin A. 54…”

Section: Manassantin a And Analogsmentioning

confidence: 99%

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Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Bhattarai

Lee

2017

Medicinal Research Reviews

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Tumor hypoxia is a common feature in most solid tumors and is associated with overexpression of the hypoxia response pathway. Overexpression of the hypoxia-inducible factor (HIF-1) protein leads to angiogenesis, metastasis, apoptosis resistance, and many other pro-tumorigenic responses in cancer development. HIF-1 is a promising target in cancer drug development to increase the patient's response to chemotherapy and radiotherapy as well as the survival rate of cancer patients. Since up to 1% of genes are hypoxia-sensitive, a target-specific HIF-1 inhibitor may be a better clinical candidate in cancer drug discovery. Though no HIF-1 inhibitor is clinically available to date, a lot of effort has been applied during the last decade in search of potent HIF-1 inhibitors. In this review, we will summarize the structure-activity relationship of ten different chemotypes reported to be HIF-1 inhibitors in the last decade (2007-2016), their mechanisms of action for HIF-1 inhibition, progress in the way of target-specific inhibitors, and problems associated with current inhibitors. It is anticipated that the results of these research on the medicinal chemistry of HIF-1 inhibitors will provide decent information in the design and development of future inhibitors.

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Section: Manassantin a And Analogsmentioning

confidence: 73%

Section: Manassantin a And Analogsmentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Bhattarai

Lee

2017

Medicinal Research Reviews

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“…Its aerial portion has been used in Korean folk medicine for the treatment of edema, gonorrhea, jaundice, and several inflammatory diseases. 10) Studies have shown that S. chinensis has various activities, including anti-inflammatory, anti-oxidant, 11,12) antiangiogenic, 13) anti-asthmatic, 14) and anti-hypertensive 15) activities, as well as therapeutic activity against atopic dermatitis. 16) Among the bioactive compounds isolated from S. chinensis, manassantin A is a major phytochemical composition that has various biological activities, including anti-inflammatory, neuroleptic, and human acyl-CoA : cholesterol acyltransferase (ACA T) inhibitory activities.…”

mentioning

confidence: 99%

Protective Effects of Manassantin A against Ethanol-Induced Gastric Injury in Rats

Song

Seo

Kim

et al. 2016

Biological & Pharmaceutical Bulletin

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Manassantin A, a neolignan isolated from Saururus chinensis, is a major phytochemical compound that has various biological activities, including anti-inflammatory, neuroleptic, and human acyl-CoA : cholesterol acyltransferase (ACAT) inhibitory activities. In this study, we investigated the protective effects of manassantin A against ethanol-induced acute gastric injury in rats. Gastric injury was induced by intragastric administration of 5 mL/kg body weight of absolute ethanol to each rat. The positive control group and the manassantin A group were given oral doses of omeprazole (20 mg/kg) or manassantin A (15 mg/kg), respectively, 1 h prior to the administration of absolute ethanol. Our examinations revealed that manassantin A pretreatment reduced ethanol-induced hemorrhage, hyperemia, and epithelial cell loss in the gastric mucosa. Manassantin A pretreatment also attenuated the increased lipid peroxidation associated with ethanolinduced acute gastric lesions, increased the mucosal glutathione (GSH) content, and enhanced the activities of antioxidant enzymes. The levels of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were clearly decreased in the manassantin A-pretreated group. In addition, manassantin A pretreatment enhanced the levels of cyclooxygenase (COX)-1, COX-2, and prostaglandin E 2 (PGE 2 ) and reduced the inducible nitric oxide synthase (iNOS) overproduction and nuclear factor kappa B (NF-κB) phosphorylation. Collectively, these results indicate that manassantin A protects the gastric mucosa from ethanol-induced acute gastric injury, and suggest that these protective effects might be associated with COX/ PGE 2 stimulation, inhibition of iNOS production and NF-κB activation, and improvements in the antioxidant and anti-inflammatory status.

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“…Manassantin A, an active component in the medicinal herb, Saururaceae, has been identified as a potent HIF-1 inhibitor with various biological activities, including neuroleptic, anti-inflammatory and antitumor effects (18,19). The present study demonstrated that a novel manassantin A derivative, X609, exerted a more potent HIF-1 inhibitory activity than that of manassantin A itself.…”

Section: Discussionmentioning

confidence: 55%

X609, a novel manassantin A derivative, exhibits antitumor activity in MG-63 human osteosarcoma cells in vitro and in vivo

Li¹,

Zhao²,

Wang³

et al. 2015

Molecular Medicine Reports

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Manassantin A has been well-established as an inhibitor of HIF-1. In the present study, a new manasantin A derivative, X609, with decreased stereochemical complexity, rendering it amenable to a simplified synthesis scheme, was synthesized and was found to increase HIF-1 inhibitory activity. X609 exhibited antiproliferative activity in a broad spectrum of tumor cell lines, via HIF-1-dependent mechanisms. X609 may induce apoptosis in MG-63 cells through activation of the mitochondrial pathway. Oral administration of X609 significantly inhibited the growth of human osteosarcomas implanted into nude mice. In light of the results of the present study, it may be possible to develop X609 for use as a novel antitumor agent, which targets human osteosarcoma.

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

Cited by 19 publications

References 23 publications

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Protective Effects of Manassantin A against Ethanol-Induced Gastric Injury in Rats

X609, a novel manassantin A derivative, exhibits antitumor activity in MG-63 human osteosarcoma cells in vitro and in vivo

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