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328543-09-5 分子结构
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2-{4-[(dimethylamino)methyl]phenyl}-1,3,10-triazatricyclo[6.4.1.0^{4,13}]trideca-2,4,6,8(13)-tetraen-9-one

ChemBase编号:72875
分子式:C19H20N4O
平均质量:320.3883
单一同位素质量:320.16371128
SMILES和InChIs

SMILES:
c12c3cccc1nc(n2CCNC3=O)c1ccc(cc1)CN(C)C
Canonical SMILES:
CN(Cc1ccc(cc1)c1nc2c3n1CCNC(=O)c3ccc2)C
InChI:
InChI=1S/C19H20N4O/c1-22(2)12-13-6-8-14(9-7-13)18-21-16-5-3-4-15-17(16)23(18)11-10-20-19(15)24/h3-9H,10-12H2,1-2H3,(H,20,24)
InChIKey:
SEKJSSBJKFLZIT-UHFFFAOYSA-N

引用这个纪录

CBID:72875 http://www.chembase.cn/molecule-72875.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
2-{4-[(dimethylamino)methyl]phenyl}-1,3,10-triazatricyclo[6.4.1.0^{4,13}]trideca-2,4,6,8(13)-tetraen-9-one
IUPAC传统名
2-{4-[(dimethylamino)methyl]phenyl}-1,3,10-triazatricyclo[6.4.1.0^{4,13}]trideca-2,4,6,8(13)-tetraen-9-one
别名
AG14361
CAS号
328543-09-5
PubChem SID
162037796
PubChem CID
9840076

数据来源

数据来源

所有数据来源 商品来源 非商品来源
数据来源 数据ID 价格
Selleck Chemicals
S2178 external link 加入购物车 请登录
数据来源 数据ID
PubChem 9840076 external link

理论计算性质

理论计算性质

JChem
Acid pKa 14.924443  质子受体
质子供体 LogD (pH = 5.5) -0.7038656 
LogD (pH = 7.4) 1.0084875  Log P 2.3521385 
摩尔折射率 105.5156 cm3 极化性 37.793793 Å3
极化表面积 50.16 Å2 可自由旋转的化学键
里宾斯基五规则 true 

分子性质

分子性质

安全信息 药理学性质 产品相关信息 生物活性(PubChem)
保存条件
-20°C expand 查看数据来源
作用靶点
PARP expand 查看数据来源
成盐信息
Free Base expand 查看数据来源

详细说明

详细说明

Selleck Chemicals Selleck Chemicals
Selleck Chemicals -  S2178 external link
Research Area
Description Cancer
Biological Activity
Description AG14361 is a potent inhibitor of PARP-1 with Ki less than 5 nM.
Targets PARP-1
IC50 <5 nm="">i) [1]
In Vitro AG14361 is at least 1000-fold more potent than the benzamides. The IC50 for AG14361 is 29 nM in permeabilized SW620 cells and 14 nM in intact SW620 cells. Crystallographic analysis of AG14361 bound to the catalytic domain of chicken PARP-1 shows that the tricyclic ring system of AG14361 is located in a pocket composed of amino acid residues Trp861, His862, Gly863, Tyr896, Phe897, Ala898, Lys903, Ser904, Tyr907, and Glu988. AG14361 forms important hydrogen bonds with Ser904 and Gly863 and a water-mediated hydrogen bond with Glu988. AG14361-induced growth inhibition is not attributed to PARP-1-related effects because maximal PARP-1 inhibition is observed at much lower concentrations (≤1 μM) than the GI50. AG14361 at 0.4 μM does not affect cancer cell gene expression or growth, but it increases the antiproliferative activity of temozolomide and topotecan, and inhibits recovery from potentially lethal γ-radiation damage in LoVo cells by 73%. In addition, 0.4 μM AG14361 does not substantially alter gene expression as shown by microarray analysis. A 17-hour exposure of A549 cells to 0.4 μM AG14361 does not change the expression of the 6800 genes. Thus, although 0.4 μM AG14361 inhibits cellular PARP-1 activity by more than 85%, it essentially does not change gene expression and cell proliferation, indicating that the cellular effects of this low concentration of AG14361 are specific for PARP-1 inhibition. Higher, growth-inhibitory concentrations of AG14361 affects gene expression, but these effects are not likely to be related to PARP-1 inhibition because cell proliferation is affected equally in PARP-/- and PARP-1+/+ cells. AG14361 is rapidly absorbed into the bloodstream and distributed to the tumor and liver with lower concentrations detected in the brain. Tissue-to-plasma concentration ratio indicates that AG14361 is retained in tumor tissue over time in both xenograft models, with tumor concentrations (≥15 μM for 2 hours) in excess of that required to inhibit PARP-1 activity in vitro. [1] AG14361 enhances temozolomide activity in all MMR-proficient cells (1.5–3.3-fold) but is more effective in MMR-deficient cells (3.7–5.2-fold potentiation), overcoming temozolomide resistance. In contrast, benzylguanine only increases the efficacy of temozolomide in MMR-proficient cells but is ineffective in MMR-deficient cells. [2] AG14361 enhances the growth-inhibitory and cytotoxic effects of topoisomerase I poisons. AG14361 increases the persistence of camptothecin-induced DNA single-strand breaks. [3]
In Vivo AG14361 treatment before irradiation statistically significantly increases the sensitivity to radiation therapy of mice bearing LoVo xenografts. AG14361 statistically significantly increases blood flow in xenografts and thus potentially increases drug delivery to tumor xenografts. In vivo, nontoxic doses of AG14361 increases the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by 2- to 3-fold. Coadministration of AG14361 with temozolomide statistically significantly increases temozolomide activity against LoVo xenografts, with the tumor growth delay being increased from 3 days to 9 days by AG14361 at 5 mg/kg and to 10 days by AG14361 at 15 mg/kg. The combination of AG14361 and temozolomide causes complete regression of SW620 xenograft tumors. PARP-1 activity, detected by pharmacodynamic assay, in SW620 xenografts is inhibited by more than 75% for at least 4 hours after intraperitoneal administration of AG14361 (10 mg/kg), consistent with the concentration of AG14361 persisting in the tumor. [1]
Clinical Trials
Features AG14361 is the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.
Protocol
Kinase Assay [1]
PARP-1 Activity Assays The activity of full-length recombinant human PARP-1 is measured in a reaction mixture containing 20 nM PARP-1, 500 μM NAD+ plus [32P]NAD+ (0.1–0.3 μCi per reaction mixture), and activated calf thymus DNA (10 μg/mL) at 25oC; the reaction is terminated after 4 minutes by adding ice-cold 10% (wt/vol) trichloroacetic acid. The reaction product [32P]ADP-ribose incorporated into acid-insoluble material is deposited onto Whatman GF/C glass fiber filters with a Bio-Dot microfiltration apparatus and quantified with a PhosphorImager. Inhibition of PARP-1 activity by AG14361 at 0–600 nM is measured, and the Ki for AG14361 is calculated by nonlinear regression analysis.
Cell Assay [1]
Cell Lines LoVo and SW620 colorectal cancer cells and A549 non–small-cell lung carcinoma cells.
Concentrations 0-20 μM
Incubation Time 5 days
Methods LoVo and SW620 colorectal cancer cells and A549 non–small-cell lung carcinoma cells are maintained in RPMI-1640 medium containing 10% fetal calf serum. Cell growth inhibition is estimated in exponentially growing LoVo, A549, and SW620 cells in 96-well plates. Cells are exposed to AG14361 (0–20 μM) alone or in the presence of 400 μM temozolomide. After 5 days of culture, these cells are fixed with 10% trichloroacetic acid and stained with sulforhodamine B. The concentration of temozolomide, topotecan, and AG14361 alone or in combination that inhibits growth by 50% (GI50) is calculated from computer-generated curves. Recovery from potentially lethal damage is measured in confluent LoVo cell cultures arrested in G1 phase to mimic the radiation-resistant quiescent cell population in tumors. Such cells are exposed to 8 Gy of γ-irradiation and then harvested and plated for colony formation assay immediately or maintained as growth-arrested confluent cultures for a 4-hour or 24-hour recovery period before harvesting and plating for the colony formation assay. Where indicated, 0.4 μM AG14361 is added 30 minutes before irradiation and is present in the recovery incubation.
Animal Study [1]
Animal Models SW620 or LoVo xenografts in CD-1 nude mice
Formulation Dissolved in dimethyl sulfoxide,to a final concentration of 1% dimethyl sulfoxide.
Doses 5 or 15 mg/kg
Administration Treated intraperitoneally, once daily for 5 days
References
[1] Calabrese CR, et al. J Natl Cancer Inst, 2004, 96(1), 56-67.
[2] Curtin NJ, et al. Clin Cancer Res, 2004, 10(3), 881-9.
[3] Smith LM, et al. Clin Cancer Res, 2005, 11(23), 8449-57.

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参考文献

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