(3Z,6Z)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylidene]-6-(phenylmethylidene)piperazine-2,5-dione

• ChemBase ID: 72559
• Molecular Formular: C19H20N4O2
• Molecular Mass: 336.3877
• Monoisotopic Mass: 336.1586259
• SMILES: c1cccc(c1)/C=c/1\[nH]c(=O)/c(=C/c2c([nH]cn2)C(C)(C)C)/[nH]c1=O
• Canonical SMILES: O=c1[nH]/c(=C\c2nc[nH]c2C(C)(C)C)/c(=O)[nH]/c/1=C\c1ccccc1
• InChI: InChI=1S/C19H20N4O2/c1-19(2,3)16-13(20-11-21-16)10-15-18(25)22-14(17(24)23-15)9-12-7-5-4-6-8-12/h4-11H,1-3H3,(H,20,21)(H,22,25)(H,23,24)/b14-9-,15-10-
• InChIKey: UNRCMCRRFYFGFX-TYPNBTCFSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (3Z,6Z)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylidene]-6-(phenylmethylidene)piperazine-2,5-dione
• IUPAC Traditional name: (3Z,6Z)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylidene]-6-(phenylmethylidene)piperazine-2,5-dione
• Synonyms: Plinabulin; NPI-2358; (3z,6z)-3-((5-tert-butyl-1h-imidazol-4-yl)methylene)-6-(phenylmethylene)-2,5-piperazinedione

Database IDs

• CAS Number: 714272-27-2
• PubChem SID: 162037484
• PubChem CID: 9949641

CALCULATED PROPERTIES

• Acid pKa: 7.047688
• H Acceptors: 3
• H Donor: 3
• LogD (pH = 5.5): 1.4622695
• LogD (pH = 7.4): 1.6651834
• Log P: 1.8065721
• Molar Refractivity: 98.0209 cm^3
• Polarizability: 36.423824 Å^3
• Polar Surface Area: 86.88 Å^2
• Rotatable Bonds: 3
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: VDA

Product Information

• Purity: 98%
• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1176

Research Area

• Description: Cancer

Biological Activity

• Description: NPI-2358 is a tubulin-depolymerizing agent and inhibits tumor cells with IC50 of 9.8~18 nM.
• Targets: Tubulin
• IC50: 9.8~18 nM ^[]
• In Vitro: NPI-2358 binds to the colchicine-binding site of tubulin and has potent inhibitory to human tumor cell lines which have overexpressed Pgp or reduced nuclear Topo II catalytic activity, with IC50 from 9.8 to 18 nM. NPI-2358 is able to rapidly induce tubulin depolymerization in HUVECs and monolayer permeability even at 20 nM. ^[1] NPI-2358 induces cell death in MM cells with IC50 of 8-10 nM, which due to trigger early mitotic arrest in MM cells. NPI-2358 also inhibits tubule formation and migration of endothelial as well as MM cells, which leads to disrupt tumor vasculature. NPI-2358 could induces cell death in patient MM (CD138+) cells without effecting viability of normal mononuclear cells. Blockade of JNK abrogates NPI-2358-induced mitotic arrest or MM cell death. ^[2]
• In Vivo: NPI-2358 (7.5 mg/kg) inhibits tumor growth in human plasmacytoma mouse xenograft models at well-tolerated doses. ^[2] NPI-2358 induces a time- and dose-dependent decrease in tumour perfusion. NPI-2358 is more sensitive to the KHT sarcoma than the C3H tumour, while radiation response could enhance the antitumor activity in both models. ^[3]
• Clinical Trials: Phase I has been completed in patients with advanced solid tumor malignancies or lymphoma.
• Features: Synthetic analog of NPI-2350 and More potent than NPI-2350

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: HT-29, PC-3, DU 145, MDA-MB-231, NCI-H292, Jurkat, MES-SA, MES-SA/Dx5, HL-60, HL-60/MX2.
• Concentrations: 2 pM - 20 μM
• Incubation Time: 24 hours.
• Methods: The adherent cells are plated in 96-well flat-bottomed plates and allowed to attach for 24 hours at 37 °C. HL-60 and HL-60/MX2 cells are plated in 96-well plates on the day of NPI-2358 addition. Serially diluted NPI-2358 is added to cells at concentrations ranging from 2 pM to 20 μM. Cells treated with a final concentration of 0.25% (v/v) DMSO serves as the vehicle control. Cell viability is assessed 48 hours later by measuring the reduction of resazurin with a fluorimeter. The IC50 value is calculated.
• Protocol: Animal Study ^[3]
• Animal Models: CDF1 mice or C3H/Hej mice.
• Formulation: Freshly prepared in a polyethylene glycol/solutol solution and diluted to the required concentration with 5% dextrose.
• Doses: ~15 mg/kg.
• Administration: Injected intraperitoneally (i.p.) in a volume of 0.02 mL/g mouse body weight in CDF1 mice and 0.01 mL/g body weight for C3H/Hej mice.

References

• References: [1] Nicholson B, et al. Anticancer Drugs, 2006, 17(1), 25-31.
• References: [2] Singh AV, et al. Blood, 2011, 117(21), 5692-5700.
• References: [3] Bertelsen LB, et al. Int J Radiat Biol, 2011, 87(11), 1126-1134.

REFERENCES

• Nicholson B, et al. Anticancer Drugs, 2006, 17(1), 25-31.
• Bertelsen LB, et al. Int J Radiat Biol, 2011, 87(11), 1126-1134.
• Singh AV, et al. Blood, 2011, 117(21), 5692-5700.