2-Methoxystypandrone

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

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

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. Several analogues of this compound were prepared. Isolation, synthesis and HRV 3C-protease structure-activity relationships of these compounds have been described.

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

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

BACKGROUND AND PURPOSE: 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-MS antagonised osteoclast development and bone resorption. EXPERIMENTAL APPROACH: RAW264.7 cells were treated with receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) to induce differentiation into osteoclasts. RT-PCR and Western blot were used to analyse osteoclast-associated gene expression and signalling pathways. KEY RESULTS: The number of multinuclear osteoclasts, actin rings and resorption pit formation were markedly inhibited by 2-MS, targeting osteoclast differentiation at an early stage and without significant cytotoxicity. The anti-resorption effect of 2-MS 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-MS. 2-MS 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. Degradation of IkappaB and phosphorylation of mitogen-activated protein kinases were also suppressed. RANKL facilitated the formation of signaling complexes of tumour necrosis factor receptor-associated factor 6 and transforming growth factor beta-activated kinase 1 (TRAF6-TAK1), important for osteoclastogenesis and formation of such signalling complexes was prevented by 2-MS. CONCLUSIONS AND IMPLICATIONS: The anti-osteoclastogenic effects of 2-MS 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.

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

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

2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model. To explore whether 2-MS could protect mice against cerebral ischemic/reperfusion (I/R)-induced brain injury, we evaluated 2-MS'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-MS (10-100 mug/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-kappaB). All of these pathological changes were diminished by 2-MS; 2-MS 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 GSK3beta which in turn upregulating beta-catenin, Bcl-2 adam11 and adamts20. We conclude that 2-MS blocks inflammatory responses by impairing NF-kappaB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-MS also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3beta to enhance beta-catenin signaling for upexpression of neuroprotective genes and proteins.

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

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

Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) or the nuclear factor-kappaB (NF-kappaB) pathway occurs frequently in cancer cells and contributes to oncogenesis. The activation of Janus kinase 2 (JAK2) and IkappaB kinase (IKK) are key events in STAT3 and NF-kappaB signaling, respectively. 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-alpha-induced NF-kappaB activation. 2-MS specifically inhibits JAK and IKKbeta kinase activities but has little effect on activities of other kinases tested. The inhibitory effects of 2-MS on STAT3 and NF-kappaB 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-kappaB signaling. We propose that the natural compound 2-MS, as a potent dual inhibitor of STAT3 and NF-kappaB pathways, is a promising anticancer drug candidate.