141400-58-0 Usage
Uses
PX 12 is an irreversible and competitive inhibitor of thioredoxin-1.
Biological Activity
px 12 is an inhibitor of thioredoxin-1 [1].thioredoxin-1 (trx-1) is a small redox protein with a conserved catalytic site and plays an important role in cells that includes the regulation of trans-activating activity and the dna binding of redox-sensitive transcription factors [1].in ht-29 human colon carcinoma cells and mcf-7 human breast cancer, px 12 prevented the hypoxia-induced increase in hif-1 protein. also, px 12 decreased inducible nitric oxide synthase, hif-1-trans-activating activity and vegf formation [2].in immunodeficient mice bearing ht-29 human colon xenografts, px 12 decreased the average tumor blood vessel permeability by 63% within 2 hours and returned to pretreatment values after 48 hours. px 12 reduced tumor-derived vegf and tumor after 24 hours. also, trx-1 showed a rapid decrease within 2 hours and maintained for 24 hours [1]. in mice bearing mcf-7 tumor xenografts, px 12 reduced hif-1ɑ and vegf protein levels [2]. in cancer patients, px-12 treatment significantly reduced the levels of trx-1 and vegf in plasma [3].
Biochem/physiol Actions
PX-12 inhibits the thioredoxin redox system and HIF-1a activity. PX 12 inhibits hypoxia-induced HIF-1a transcriptional activity (IC50 11 nM) and proliferation of HT29 and MCF-7 tumor cells (IC50 1.9 and 0.9 uM, respectively).
references
[1]. jordan bf, runquist m, raghunand n, et al. the thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (px-12) decreases vascular permeability in tumor xenografts monitored by dynamic contrast enhanced magnetic resonance imaging. clin cancer res, 2005, 11(2 pt 1): 529-536.[2]. welsh sj, williams rr, birmingham a, et al. the thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation. mol cancer ther, 2003, 2(3): 235-243.[3]. baker af, dragovich t, tate wr, et al. the antitumor thioredoxin-1 inhibitor px-12 (1-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and vegf levels in cancer patient plasma. j lab clin med, 2006, 147(2): 83-90.
Check Digit Verification of cas no
The CAS Registry Mumber 141400-58-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,1,4,0 and 0 respectively; the second part has 2 digits, 5 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 141400-58:
(8*1)+(7*4)+(6*1)+(5*4)+(4*0)+(3*0)+(2*5)+(1*8)=80
80 % 10 = 0
So 141400-58-0 is a valid CAS Registry Number.
InChI:InChI=1/C7H12N2S2/c1-3-6(2)10-11-7-8-4-5-9-7/h4-6H,3H2,1-2H3,(H,8,9)
141400-58-0Relevant articles and documents
Synthesis and evaluation of imidazolyl disulfides for selective cytotoxicity to hypoxic EMT6 tumor cells in vitro
Kirkpatrick,Jimale,King,Chen
, p. 33 - 37 (1992)
Two series of disulfides were synthesized and evaluated in vitro for selective hypoxic tumor cell cytotoxicity using EMT6 cells. While the series of alkyl 5-nitrobenzimidazolyl disulfides displayed no selectivity, two alkyl imidazolyl disulfides, devoid of a nitro function, showed preferential toxicity to EMT6 cells treated under hypoxic conditions. Select agents of the alkyl imidazolyl series were found to deplete cellular glutathione (GSH) while the corresponding alkyl nitrobenzimidazolyl derivatives did not. One disulfide displaying selective hypoxic cell toxicity, n-butyl 2-imidazolyl disulfide, 10, caused significantly greater depletion of GSH under aerobic conditions. Removal of cellular GSH with buthionine sulfoximine (BSO) prior to exposure to 10 caused an increase in its toxicity and a loss of any differential between aerobic and hypoxic conditions. It is speculated that the diminished aerobic vs hypoxic toxicity of the agent toward EMT6 cells is due to a greater ability of 10 to interact with GSH under aerobic conditions as reflected by the greater GSH depletion.
Selective inhibition of extracellular thioredoxin by asymmetric disulfides
Diraimondo, Thomas R.,Plugis, Nicholas M.,Jin, Xi,Khosla, Chaitan
, p. 1301 - 1310 (2013/04/10)
Whereas the role of mammalian thioredoxin (Trx) as an intracellular protein cofactor is widely appreciated, its function in the extracellular environment is not well-understood. Only few extracellular targets of Trx-mediated thiol-disulfide exchange are known. For example, Trx activates extracellular transglutaminase 2 (TG2) via reduction of an intramolecular disulfide bond. Because hyperactive TG2 is thought to play a role in various diseases, understanding the biological role of extracellular Trx may provide critical insight into the pathogenesis of these disorders. Starting from a clinical-stage asymmetric disulfide lead, we have identified analogs with >100-fold specificity for Trx. Structure-activity relationship and computational docking model analyses have provided insights into the features important for enhancing potency and specificity. The most active compound identified had an IC 50 below 0.1 μM in cell culture and may be appropriate for in vivo use to interrogate the role of extracellular Trx in health and disease.
