675576-98-4
675576-98-4 structure
- Name: Nutlin-3a
- Chemical Name: 2-Piperazinone, 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]
- CAS Number: 675576-98-4
- Molecular Formula: C30H30Cl2N4O4
- Molecular Weight: 581.490
- Catalog: Biochemical Inhibitor Apoptosis Mdm2 inhibitor
- Create Date: 2016-05-02 04:20:14
- Modify Date: 2024-01-02 20:12:18
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Nutlin 3a is an active enantiomer of Nutlin-3, acts as a murine double minute (MDM2) antagonist that inhibits MDM2-p53 interactions and stabilizes the p53 protein, and thereby induces cell cycle arrest and apoptosis.
| Name | 2-Piperazinone, 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl] |
|---|---|
| Synonyms |
Nutlin-3
2-Piperazinone, 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]- 4-({4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazol-1-yl}carbonyl)piperazin-2-one 4-({(4S,5R)-4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazol-1-yl}carbonyl)piperazin-2-one UNII:53IA0V845C 2-Piperazinone, 4-[[4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]- Piperazinone, 4-[[(4R,5S)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-, rel-;4-[4,5-Bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one 4-{[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazol-1-yl]carbonyl}-2-piperazinone Nutlin-3a 4-{[(4S,5R)-4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazol-1-yl]carbonyl}-2-piperazinone Nutlin (3a) NUTLIN 3A |
| Description | Nutlin 3a is an active enantiomer of Nutlin-3, acts as a murine double minute (MDM2) antagonist that inhibits MDM2-p53 interactions and stabilizes the p53 protein, and thereby induces cell cycle arrest and apoptosis. |
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| Related Catalog | |
| Target |
MDM2-p53[1] |
| In Vitro | Nutlin 3a (Nutlin-3a) is a therapeutic which inhibits MDM2, activates wild-type p53, and induces apoptosis-as a therapeutic compound for TP53 wild-type ovarian carcinomas. Three cell lines (HOC-7, OVCA429 and A2780) with wild-type TP53 are highly sensitive to Nutlin 3a (IC50=4 to 6 μM). SKOV3 cells have an IC50 of 38 μM to Nutlin 3a. The two remaining ovarian clear cell lines (TOV21G and OVAS), both with TP53 wild-type, are relatively more sensitive to growth inhibition with Nutlin 3a (IC50=14 and 25 μm respectively) than the TP53 mutant cell lines[1]. Nutlin 3a (Nutlin-3a) is the active enantiomer of Nutlin-3. Nutlin 3a is a highly selective MDM2 antagonist and p53 inducer. Seven days of incubation with 10 μM Nutlin 3a leads to >90% inhibition of NIH/3T3 cells’growth but does not affect the proliferation of MEF in which both targets of the drug are eliminated. Nutlin 3a effectively arrestes cell-cycle progression in all cell lines, depleting the S-phase compartment to 0.2-2% and increasing the G1- and G2/M-phase compartments, indicating G1 and G2 arrest. The p53 targets p21 and MDM2 are elevated significantly 3 h after Nutlin 3a addition and reach maximal levels at 8 h. Nutlin 3a induces apoptosis in ≈60% of SJSA-1 and MHM cells after 40 h, which increase further after 60 h (85% and 65%, respectively)[2]. |
| In Vivo | Nutlin 3a (Nutlin-3a) is efficacious in all models with average tumor growth inhibition ≥98%. Nutlin 3a suppresses xenograft growth in a dose-dependent fashion with the highest dose (200 mg/kg) showing a substantial tumor shrinkage (eight partial and one full regressions). The established SJSA-1 and MHM osteosarcoma xenografts with Nutlin 3a causes extensive tumor regression[2]. |
| Cell Assay | All 15 cell lines are plated at a density of 1×103 cells per well in 96-well plates. After 24h, media is exchanged and cells are treated with incremental concentrations of Nutlin 3a (1 μM, 5 μM, 10 μM, 25 μM, 50 μM, and 70 μM). After 72 h of incubation, WST-1 is added to each well, and a microplate reader is used at an absorbance of 450 nm to measure the number of remaining viable cells. Experiments are repeated with smaller titrations of Nutlin 3a as needed to determine the exact IC50 of cell lines. The IC50 is defined. Cell lines are again plated in a manner identical to above and treated with Nutlin 3a at their respective IC50, and WST-1 is added with cell viability measurement at 24, 48, and 72h[1]. |
| Animal Admin | Mice[2] Nude mice bearing s.c. tumor xenografts (10 mice per group in the SJSA-1, LnCaP, and 22Rv1 study and 15 mice per group in the MHM study) are dosed orally twice daily with Nutlin 3a (50-200 mg/kg) or vehicle (1% Klucel, 0.1% Tween 80) for 2 weeks (22Rv1 and LnCap) or 3 weeks (SJSA-1 and MHM). Tumor volume is measured with a caliper and calculated. For Western blot analysis, nude mice with established SJSA-1 tumors (200-400 mm3, three animals per group are treated with three doses of Nutlin 3a at 150 mg/kg (at 0, 8, and 24 h), and tumors are harvested 3 h after the last dose. Tumor samples are flash-frozen and processed[2]. |
| References |
| Density | 1.4±0.1 g/cm3 |
|---|---|
| Molecular Formula | C30H30Cl2N4O4 |
| Molecular Weight | 581.490 |
| Exact Mass | 580.164429 |
| PSA | 83.47000 |
| LogP | 2.77 |
| Appearance | white to beige |
| Index of Refraction | 1.648 |
| Storage condition | ?20°C |
| Water Solubility | DMSO: soluble5mg/mL, clear |
| Symbol |
GHS07 |
|---|---|
| Signal Word | Warning |
| Hazard Statements | H302 |
| Precautionary Statements | P301 + P312 + P330 |
| Hazard Codes | Xn |
| Risk Phrases | 22 |
| RIDADR | NONH for all modes of transport |