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

• ChemBase编号: 72559
• 分子式: C19H20N4O2
• 平均质量: 336.3877
• 单一同位素质量: 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

名称和登记号

名称

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

登记号

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

理论计算性质

• Acid pKa: 7.047688
• 质子受体: 3
• 质子供体: 3
• LogD (pH = 5.5): 1.4622695
• LogD (pH = 7.4): 1.6651834
• Log P: 1.8065721
• 摩尔折射率: 98.0209 cm^3
• 极化性: 36.423824 Å^3
• 极化表面积: 86.88 Å^2
• 可自由旋转的化学键: 3
• 里宾斯基五规则: true

分子性质

理化性质

• 溶解度: DMSO

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: VDA

产品相关信息

• 纯度: 98%
• 成盐信息: Free Base

详细说明

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.

参考文献

• 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.