C-DIM12 - CAS 178946-89-9
Catalog number: 178946-89-9
Category: Inhibitor
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C-DIM12 is a novel synthetic activator of Nurr1. C-DIM12 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro. .
Solid powder
C-DIM12; C-DIM 12; C-DIM-12.
Soluble in DMSO, not in water
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Shelf Life:
2 years if stored properly
Canonical SMILES:
1.Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson's disease.
De Miranda BR;Popichak KA;Hammond SL;Miller JA;Safe S;Tjalkens RB Toxicol Sci. 2015 Feb;143(2):360-73. doi: 10.1093/toxsci/kfu236. Epub 2014 Nov 17.
The orphan nuclear receptor NR4A2 (Nurr1) constitutively regulates inflammatory gene expression in glial cells by suppressing DNA binding activity of NF-κB. We recently reported that novel 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methane (C-DIM) compounds that activate NR4A family nuclear receptors in cancer lines also suppress inflammatory gene expression in primary astrocytes and prevent loss of dopaminergic neurons in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp). In this study, we postulated that the basis for this neuroprotection involves blockade of glial activation and subsequent expression of NF-κB-regulated inflammatory genes. To examine this mechanism, we treated transgenic NF-κB/EGFP reporter mice with MPTPp for 7 days (MPTPp7d) followed by daily oral gavage with either vehicle (corn oil; MPTPp14d) or C-DIMs containing p-methoxyphenyl (C-DIM5), p-hydroxyphenyl (C-DIM8), or p-chlorophenyl (C-DIM12) groups. Each compound conferred significant protection against progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), even when given after 7 days of dosing with MPTPp. C-DIM12 had the greatest neuroprotective activity in MPTPp-treated mice, and was also the most potent compound in suppressing activation of microglia and astrocytes, expression of cytokines and chemokines in quantitative polymerase chain reaction (qPCR) array studies, and in reducing expression of NF-κB/EGFP in the SN.
2.A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro.
Hammond SL;Safe S;Tjalkens RB Neurosci Lett. 2015 Oct 21;607:83-89. doi: 10.1016/j.neulet.2015.09.015. Epub 2015 Sep 14.
Degeneration of dopaminergic neurons in Parkinson's disease (PD) is associated with decreased expression of the orphan nuclear receptor Nurr1 (NR4A2), which is critical for both homeostasis and development of dopamine (DA) neurons. The synthetic, phytochemical-based compound, 1,1-bis (3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) activates Nurr1 in cancer cells and prevents loss of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. In the present study, we examined the capacity of C-DIM12 to induce expression of Nurr1-regulated genes in two dopaminergic neuronal cell lines (N2A, N27) and to protect against 6-hydroxydopamine (6-OHDA) neurotoxicity. C-DIM12 induced expression of Nurr1-regulated genes that was abolished by Nurr1 knockdown. C-DIM12 increased expression of transfected human Nurr1, induced Nurr1 protein expression in primary dopaminergic neurons and enhanced neuronal survival from exposure to 6-OHDA. These data indicate that C-DIM12 stimulates neuroprotective expression Nurr1-regulated genes in DA neurons.
3.Neuroprotective efficacy and pharmacokinetic behavior of novel anti-inflammatory para-phenyl substituted diindolylmethanes in a mouse model of Parkinson's disease.
De Miranda BR;Miller JA;Hansen RJ;Lunghofer PJ;Safe S;Gustafson DL;Colagiovanni D;Tjalkens RB J Pharmacol Exp Ther. 2013 Apr;345(1):125-38. doi: 10.1124/jpet.112.201558. Epub 2013 Jan 14.
There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain. The present studies examined a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compounds that display anti-inflammatory and neuroprotective efficacy in vitro. We postulated that the pharmacokinetic behavior of C-DIM compounds after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson's disease. Pharmacokinetics and metabolism of 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (C-DIM5), 1,1-bis(3'-indolyl)-1-(phenyl)methane, 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (C-DIM8), and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) were determined in plasma and brain of C57Bl/6 mice after oral and intravenous administration at 10 and 1 mg/Kg, respectively. Putative metabolites were measured in plasma, liver, and urine. C-DIM compounds given orally displayed the highest area under the curve, Cmax, and Tmax levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compounds tested. Oral bioavailability of each compound ranged from 6% (C-DIM8) to 42% (C-DIM12).
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