2-Methoxystypandrone

Biochem Pharmacol. 2014 Feb 1;87(3):502-14.

2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke.[Pubmed: 24342702 ]

2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model.
METHODS AND RESULTS:
To explore whether 2-Methoxystypandrone could protect mice against cerebral ischemic/reperfusion (I/R)-induced brain injury, we evaluated 2-Methoxystypandrone's protective effects on an acute ischemic stroke by inducing a middle cerebral artery occlusion/reperfusion (MCAO) injury in murine model. Treatment of mice that have undergone I/R injury with 2-Methoxystypandrone (10-100 μg/kg, i.v.) at 2 h after MCAO enhanced survival rate and ameliorated neurological deficits, brain infarction, neural dysfunction and massive oxidative stress, due to an enormous production of free radicals and breakdown of blood-brain barrier (BBB) by I/R injury; this primarily occurred with extensive infiltration of CD11b-positive inflammatory cells and upexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and p65 nuclear factor-kappa B (NF-κB). All of these pathological changes were diminished by 2-Methoxystypandrone; 2-Methoxystypandrone also intensively limited cortical infarction and promoted upexpression of neurodevelopmental genes near peri-infarct cortex and endogenous neurogenesis near subgranular zone of hippocampal dentate gyrus and the subventricular zone, most possibly by inactivation of GSK3β which in turn upregulating β-catenin, Bcl-2 adam11 and adamts20.
CONCLUSIONS:
We conclude that 2-Methoxystypandrone blocks inflammatory responses by impairing NF-κB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-Methoxystypandrone also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3β to enhance β-catenin signaling for upexpression of neuroprotective genes and proteins.

Cancer Sci. 2014 Apr;105(4):473-80.

2-Methoxystypandrone inhibits signal transducer and activator of transcription 3 and nuclear factor-κB signaling by inhibiting Janus kinase 2 and IκB kinase.[Pubmed: 24450414]

Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) or the nuclear factor-κB (NF-κB) pathway occurs frequently in cancer cells and contributes to oncogenesis. The activation of Janus kinase 2 (JAK2) and IκB kinase (IKK) are key events in STAT3 and NF-κB signaling, respectively.
METHODS AND RESULTS:
We have identified 2-Methoxystypandrone (2-MS) from a traditional Chinese medicinal herb Polygonum cuspidatum as a novel dual inhibitor of JAK2 and IKK. 2-MS inhibits both interleukin-6-induced and constitutively-activated STAT3, as well as tumor necrosis factor-α-induced NF-κB activation. 2-MS specifically inhibits JAK and IKKβ kinase activities but has little effect on activities of other kinases tested. The inhibitory effects of 2-MS on STAT3 and NF-κB signaling can be eliminated by DTT or glutathione and can last for 4 h after a pulse treatment. Furthermore, 2-MS inhibits growth and induces death of tumor cells, particularly those with constitutively-activated STAT3 or NF-κB signaling.
CONCLUSIONS:
We propose that the natural compound 2-MS, as a potent dual inhibitor of STAT3 and NF-κB pathways, is a promising anticancer drug candidate.

Br J Pharmacol. 2010 Sep;161(2):321-35.

2-Methoxystypandrone represses RANKL-mediated osteoclastogenesis by down-regulating formation of TRAF6-TAK1 signalling complexes.[Pubmed: 20735418]

2-Methoxystypandrone (2-MS) is a naphthoquinone isolated from Polygonum cuspidatum, a Chinese herb used to treat bone diseases. Here we have determined whether 2-Methoxystypandrone antagonised osteoclast development and bone resorption.
METHODS AND RESULTS:
The number of multinuclear osteoclasts, actin rings and resorption pit formation were markedly inhibited by 2-Methoxystypandrone , targeting osteoclast differentiation at an early stage and without significant cytotoxicity. The anti-resorption effect of 2-Methoxystypandrone was accompanied by decreasing dendritic cell-specific transmembrane protein and matrix metalloproteinase-9 (MMP-9) mRNA expression. RANKL-increased MMP-9 gelatinolytic activity was also attenuated by concurrent, but not by subsequent addition of 2-Methoxystypandrone . 2-Methoxystypandrone markedly inhibited not only the RANKL-triggered nuclear translocations of NF-kappaB, c-Fos and nuclear factor of activated T cells c1 (NFATc1), but also the subsequent NFATc1 induction.Important for osteoclastogenesis and formation of such signalling complexes was prevented by 2-Methoxystypandrone.
CONCLUSIONS:
The anti-osteoclastogenic effects of 2-Methoxystypandrone could reflect the block of RANKL-induced association of TRAF6-TAK1 complexes with consequent decrease of IkappaB-mediated NF-kappaB and mitogen-activated protein kinases-mediated c-Fos activation pathways and suppression of NFATc1 and other gene expression, essential for bone resorption.

Bioorg Med Chem Lett. 2001 Dec 17;11(24):3143-6.

Discovery, total synthesis, HRV 3C-protease inhibitory activity, and structure-activity relationships of 2-methoxystypandrone and its analogues.[Pubmed: 11720861]

METHODS AND RESULTS:
2-Methoxystypandrone, a naphthoquinone, was isolated from a Chinese herb Polygonum cuspidatum by bioassay guided fractionation using HRV 3C-protease assay. It showed an IC(50) value of 4.6 microM and is moderately selective. A new 10-step, total synthesis of 2-Methoxystypandrone was accomplished in 45% overall yield using a Diels-Alder approach.
CONCLUSIONS:
Several analogues of this compound were prepared. Isolation, synthesis and HRV 3C-protease structure-activity relationships of these compounds have been described.