| Identification | Back Directory | [Name]
PRIMA-1 | [CAS]
5608-24-2 | [Synonyms]
PRIMA-1
NSC-281668
2,2-dimethylolquinuclidin-3-one
PRIMA-1 - CAS 5608-24-2 - Calbiochem
2-Bis(hydroxymethyl)-3-quinuclidinone
2,2-BIS(HYDROXYMETHYL)-3-QUINUCLIDINONE
P53 REACTIVATION AND INDUCTION OF MASSIVE APOPTOSIS
2,2-BIS(HYDROXYMETHYL)-1-AZABICYCLO[2,2,2]OCTAN-3-ONE
7,7-bis(hydroxymethyl)-1-azabicyclo[2.2.2]octan-8-one
1-Azabicyclo[2.2.2]octan-3-one, 2,2-bis(hydroxymethyl)- | [Molecular Formula]
C9H15NO3 | [MDL Number]
MFCD04974196 | [MOL File]
5608-24-2.mol | [Molecular Weight]
185.22 |
| Chemical Properties | Back Directory | [Melting point ]
146-147 °C | [Boiling point ]
353.7±17.0 °C(Predicted) | [density ]
1.32±0.1 g/cm3(Predicted) | [storage temp. ]
Inert atmosphere,2-8°C | [solubility ]
H2O: >10mg/mL | [form ]
solid | [pka]
13.68±0.10(Predicted) | [color ]
white to off-white | [Water Solubility ]
Soluble in water at 10mg/ml | [Sensitive ]
Light Sensitive | [InChI]
1S/C9H15NO3/c11-5-9(6-12)8(13)7-1-3-10(9)4-2-7/h7,11-12H,1-6H2 | [InChIKey]
RFBVBRVVOPAAFS-UHFFFAOYSA-N | [SMILES]
OCC1(CO)N2CC[C@@H](CC2)C1=O |
| Safety Data | Back Directory | [Hazard Codes ]
Xn | [Risk Statements ]
22-43 | [Safety Statements ]
36/37 | [WGK Germany ]
3 | [Storage Class]
11 - Combustible Solids | [Hazard Classifications]
Acute Tox. 4 Oral
Resp. Sens. 1 |
| Hazard Information | Back Directory | [Uses]
PRIMA-1 is a reactivator of p53 and inducer of apoptosis. | [Definition]
ChEBI: 2,2-bis(hydroxymethyl)-1-azabicyclo[2.2.2]octan-3-one is a member of quinuclidines and a cyclic ketone. | [Biological Activity]
Selectively restores mutant p53 activity in tumor cells via activation of Bax and PUMA. Induces apoptosis and inhibits growth of human tumors with mutant p53. | [Synthesis]
Example 1: Synthesis of 2,2-bis(hydroxymethyl)-1-azabicyclo[2.2.2]octan-3-one (2) (intermediate)
3-Quinuclidinone hydrochloride (1) (commercially available, 16.9 g, 0.1 mol) was reacted with formalin (37% w/w, 150 mL, 2.0 mol) in the presence of potassium carbonate (15.9 g, 0.11 mol) for 1 hr at 52°C until the feedstock was consumed. After completion of the reaction, the conversion was monitored by LC-MS. The aqueous reaction mixture was extracted with dichloromethane (4 x 80 mL), the organic phases were combined and dried with anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, heptane (500 mL) was added to the residue and heated for 1 h. The hot heptane extract was expelled. Benzene (400 mL) was added to the residue and heating was continued for 8 hours. The reaction mixture was filtered from the polymer formed during heating to give a clarified solution which was subsequently evaporated to dryness. The residue was extracted with boiling heptane (300 mL) and after decanting the heptane, boiling benzene (400 mL) was added to the residue. After filtration and cooling to 6 °C, the solid precipitate was separated by filtration to give 5.1 g of 2,2-bis(hydroxymethyl)-1-azabicyclo[2.2.2]octan-3-one (2) (melting point: 136-138 °C). A second batch of product was isolated from the combined mother liquor and heptane extract to give 2.9 g of product. The total yield was 37%. | [in vitro]
the substantial increase in saos-2-his-273-cells death could be noticed after being treated with 125 μm prima-1 for 48 hours. tunel staining revealed that such tumor-cell death was primarily triggered by apoptosis. prima-1 could also restore the transcriptional transactivation function to mutant p53 in vitro. [2] | [in vivo]
to assess the effect of prima-1 on human tumor xenografts, mice were inoculated with saos-2-his-273 cells expressing mutant p53. the mice then received prima-1 treatment at intra-tumor does of 20 mg/kg or i.v. doses of 20 and 100 mg/kg twice a day for three days. compared with the control group, the average tumor volume decreased from 555.7 mm3 to 11.7 (100 mg/kg) and 53 (20 mg/kg) mm3 after i.v. injections of prima-1. intra-tumor injections of prima-1 also decreased the average tumor volume to 5.3 mm3. [2] | [IC 50]
the value varied among different tumor type. in saos-2-his-273 cells, prima-1 induced cell death with an ic50 of over 15 m. | [storage]
Store at +4°C | [References]
[1] bykov v, issaeva n, zache n, shilov a, hultcrantz m, bergman j, selivanova g, wiman kg. reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. j biol chem. 2005 aug; 280(34): 30384–91.
[2] bykov v, issaeva n, shilov a, hultcrantz m, pugacheva e, chumakov p, bergman j, wiman kg, selivanova g. restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. nat med. 2002 mar; 8(3):282-8.
[3] lehmann s, bykov v, ali d, andren o, cherif h, tidefelt u, uggla b, yachnin j, juliusson g, moshfegh a, paul c, wiman kg, andersson po. targeting p53 in vivo: a first-in-human study with p53-targeting compound apr-246 in refractory hematologic malignancies and prostate cancer. j clin oncol. 2012. doi: 10.1200/jco.2011.40.7783. |
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