1-(2-methoxyethyl)-2-methyl-3-(pyrazin-2-ylmethyl)-4H,9H-naphtho[2,3-d]imidazole-4,9-dione bromide

• ChemBase编号: 72528
• 分子式: C20H20BrN4O3-
• 平均质量: 444.3018
• 单一同位素质量: 443.07187752
• SMILES: c1ccc2c(c1)C(=O)C1=C(C2=O)N(C(N1Cc1nccnc1)C)CCOC.[Br-]
• Canonical SMILES: COCCN1C(C)N(C2=C1C(=O)c1c(C2=O)cccc1)Cc1cnccn1.[Br-]
• InChI: InChI=1S/C20H20N4O3.BrH/c1-13-23(9-10-27-2)17-18(24(13)12-14-11-21-7-8-22-14)20(26)16-6-4-3-5-15(16)19(17)25;/h3-8,11,13H,9-10,12H2,1-2H3;1H/p-1
• InChIKey: OOLCTHGNPMKPRV-UHFFFAOYSA-M

名称和登记号

名称

• IUPAC标准名: 1-(2-methoxyethyl)-2-methyl-3-(pyrazin-2-ylmethyl)-4H,9H-naphtho[2,3-d]imidazole-4,9-dione bromide
• IUPAC传统名: 1-(2-methoxyethyl)-2-methyl-3-(pyrazin-2-ylmethyl)naphtho[2,3-d]imidazole-4,9-dione bromide
• 别名: YM155

登记号

• CAS号: 781661-94-7
• PubChem SID: 162037453
• PubChem CID: 46931000

理论计算性质

• 质子受体: 7
• 质子供体: 0
• LogD (pH = 5.5): -1.918101
• LogD (pH = 7.4): -1.9181
• Log P: -1.9181
• 摩尔折射率: 132.4457 cm^3
• 极化性: 37.96453 Å^3
• 极化表面积: 119.75 Å^2
• 可自由旋转的化学键: 5
• 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: Survivin

产品相关信息

• 成盐信息: Bromide

详细说明

Selleck Chemicals - S1130

Research Area

• Description: Non-Hodgkin's lymphoma,Malignant melanoma,cancer

Biological Activity

• Description: YM155 is a potent IAP (inhibitor of apoptosis proteins) inhibitor for survivin with IC50 of 0.54 nM.
• Targets: Survivin
• IC50: 0.54 nM ^[1]
• In Vitro: YM155 is not sensitive to survivn gene promoter-driven luciferase reporter activity even at 30 μM. YM155 significantly inhibits endogenous survivin expression in PC-3 and PPC-1 human HRPC cells with deficient p53 through transcriptional inhibition of the survivin gene promoter. On the contrary YM155 shows no sufficient effect on protein expression of c-IAP2, XIAP, Bcl-2, Bcl-xL, Bad, α-actin, and β-tubulin at 100 nM. YM155 indicates great apoptosis in human cancer cell lines including PC-3 and PPC-1 with a concomitant increase in caspase-3 activity. YM155 potently inhibits human cancer cell lines (mutated or truncated p53) including PC-3, PPC-1, DU145, TSU-Pr1, 22Rv1, SK-MEL-5 and A375 with IC50 from 2.3 to 11 nM, respectively. ^[1] YM155 increases the sensitivity of NSCLC cells to γ-radiation. The combination of YM155 and γ-radiation increases both the number of apoptotic cells and the activity of caspase-3. YM155 delays the repair of radiation-induced double-strand breaks in nuclear DNA. ^[2]
• In Vivo: YM155 completely inhibits the tumor growth of PC-3 s.c. xenografted prostate tumors at doses of 3 and 10 mg/kg, without body weight loss and blood cell count decrease. Pharmacokinetic analysis shows that YM155 is highly distributed to tumor tissue. Moreover, YM155 shows 80% TGI at a dose of 5 mg/kg in PC-3 orthotopic xenografts. ^[1] The combination therapy with YM155 and γ-radiation shows great antitumor activity against H460 or Calu6 xenografts in nude mice. ^[2]
• Clinical Trials: YM155 is currently in Phase II clinical trial in advanced non-small cell lung carcinoma.

Protocol

• Protocol: Kinase Assay ^[1]
• Promoter-luciferase reporter assay: A 2,767-bp sequence of human survivin gene promoter is isolated from human genomic DNA by PCR using Pyrobest polymerase and the following primers: 5’-GCGCGCTCGAGTCTAGACATGCGGATATATTC-3’ and 5’-GCGCGAA-GCTTTGGCGGTTAATGGCGCGC-3’. The resulting PCR fragment is digested with XhoI/HindIII and ligated into the XhoI/HindIII cleavage site of the pGL3-Basic vector. The resulting plasmid is named pSUR-luc. DNA sequencing is done on all amplified sequences by a DNA sequencer. The activity of pSUR-luc is confirmed by luciferase assay with transiently transfected HeLa-S3 cells. Luciferase assay is done. The pGL3 control vector, which contains the SV40 promoter and enhancer sequences, is used. HeLa cells are stably transfected with pSUR-luc and pSV2bsr by Lipofect-AMINE 2000. After blasticidin selection at 10 μg/mL, a single colony is chosen based on appropriate luciferase signals and genetic stability over time and named HeLa-SURP-luc. CHO cells are stably transfected with pGL3-control and pSV2bsr. After blasticidin selection at 10 μg/mL, a single colony is chosen based on appropriate luciferase signals and genetic stability over time and named CHO-SV40-luc. Stocked cells from the HeLa-SURP-luc and CHO-SV40-luc clones are used for chemical screening and characterization of YM155. YM155 in DMSO are added to the cells, which had been seeded the previous day on 96-well plastic plates at 5 × 10^3 per well. Luciferase activity is measured 24 hours later. IC50 is calculated by logistic analysis.
• Protocol: Cell Assay ^[1]
• Cell Lines: Hormone refractory prostate cancer cell lines (PC-3, PPC-1, DU145, TSU-Pr1 and 22Rv1) and malignant melanoma cell lines (SK-MEL-5 and A375)
• Concentrations: ~ 100 nM
• Incubation Time: 48 hours
• Methods: Cells are seeded in 96-well plates at a density of 5-40 × 10^3. YM155 is dissolved in DMSO and added to cells for 48 hours. Then the cell count is determined by sulforhodamine B assay.
• Protocol: Animal Study ^[1]
• Animal Models: PC-3 s.c. (orthotopic) xenografts in male nude mice (BALB/c nu/nu)
• Formulation: Dissolved and diluted in saline immediately before administration
• Doses: 5 mg/kg
• Administration: Subcutaneous injection as a 3-day continuous infusion per week for 3 weeks by an implanted micro-osmotic pump

References

• References: [1] Nakahara T, et al. Cancer Res, 2007, 67(17), 8014-8021.
• References: [2] Iwasa T, et al. Clin Cancer Res, 2008, 14(20), 6496-6504.

参考文献

• Nakahara T, et al. Cancer Res, 2007, 67(17), 8014-8021.
• Iwasa T, et al. Clin Cancer Res, 2008, 14(20), 6496-6504.