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475489-16-8 分子结构
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5-[3-(benzyloxy)phenyl]-7-[(1s,3s)-3-(azetidin-1-ylmethyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

ChemBase编号:73155
分子式:C27H29N5O
平均质量:439.55206
单一同位素质量:439.23721057
SMILES和InChIs

SMILES:
c1cc(cc(c1)OCc1ccccc1)c1cn(c2c1c(ncn2)N)[C@@H]1C[C@@H](C1)CN1CCC1
Canonical SMILES:
Nc1ncnc2c1c(cn2[C@@H]1C[C@@H](C1)CN1CCC1)c1cccc(c1)OCc1ccccc1
InChI:
InChI=1S/C27H29N5O/c28-26-25-24(21-8-4-9-23(14-21)33-17-19-6-2-1-3-7-19)16-32(27(25)30-18-29-26)22-12-20(13-22)15-31-10-5-11-31/h1-4,6-9,14,16,18,20,22H,5,10-13,15,17H2,(H2,28,29,30)/t20-,22+
InChIKey:
AECDBHGVIIRMOI-GRGXKFILSA-N

引用这个纪录

CBID:73155 http://www.chembase.cn/molecule-73155.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
5-[3-(benzyloxy)phenyl]-7-[(1s,3s)-3-(azetidin-1-ylmethyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine
IUPAC传统名
5-[3-(benzyloxy)phenyl]-7-[(1s,3s)-3-(azetidin-1-ylmethyl)cyclobutyl]pyrrolo[2,3-d]pyrimidin-4-amine
别名
AEW541
NVP-AEW541
CAS号
475489-16-8
PubChem SID
162038075
PubChem CID
11476171

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
S1034 external link 加入购物车 请登录
数据来源 数据ID
PubChem 11476171 external link

理论计算性质

理论计算性质

JChem
质子受体 质子供体
LogD (pH = 5.5) -0.7197423  LogD (pH = 7.4) 2.015645 
Log P 4.1548033  摩尔折射率 132.7197 cm3
极化性 52.0621 Å3 极化表面积 69.2 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
IGF-1R 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 -  S1034 external link
Biological Activity
Description NVP-AEW541 is a potent inhibitor of IGF-IR with IC50 of 86 nM.
Targets IGF-IR
IC50 86 nM [1]
In Vitro NVP-AEW541 also inhibits InsR, Tek, Flt1 and Flt3 with IC50 of 140 nM, 530 nM, 600 nM and 420 nM in purified kinases/recombinant kinase domains assay. NVP-AEW541 is more selective and shows 27-fold more potent than InsR at the cellular level. NVP-AEW541 suppresses the IGF-I-mediated survival, soft agar and proliferation of MCF-7 cells with IC50 of 0.162 μM, 0.105 μM and 1.64 μM, respectively. NVP-AEW541 also reduces the level of phospho-IGF-IR and phospho-PKB in NWT-21 cells. [1] NVP-AEW541 shows growth inhibitory effect on TC-71 musculoskeletal sarcoma cells in low-serum medium as well as in 10% FBS–containing medium. NVP-AEW541 inhibits cell cycle progression and induces specific G1 arrest in sarcoma cell lines (TC-71, SK-N-MC, SaoS-2, RD/18 and RH4). [2] NVP-AEW541 could inhibit the growth of human neuroblastoma cells with IC50 of 0.4-6.8 μM. An increase in the hypodiploid fraction and the depletion of the S and G2-M compartments could be detected in these cell lines. NVP-AEW541-driven inhibition of IGF-IR causes a reduction of phosphorylation of Akt, but not of Erk1 and Erk2 in neuroblastoma cells. [3] NVP-AEW541 inhibits glioma cell growth and disrupts the autocrine loop initiated by HIF1α stabilization. [4] A recent study shows that NVP-AEW541 suppresses the proliferation and viability of PC3, DU145, and 22Rv1 prostate cancer cells, without necessarity of associated cell death. NVP-AEW541 decreases phospho-Akt levels in 22Rv1 and DU415 cells but not PC3 cells, without affecting total Akt levels, which shows that PTEN status could determine the effectiveness of NVP-AEW541 with essential Akt. NVP-AEW541-induced radiosensization is dependent on Akt activation status. NVP-AEW541 could increase the H2AX phosphorylation (a measure of DSBs) in PC3, DU145, and 22Rv1 cells. [5]
In Vivo NVP-AEW541 (50 mg/kg, p.o.) results in abrogation of basal and IGF-I-induced receptor, and PKB and MAPK phosphorylation, with T/C value of 14% in the NWT-21 tumor xenograft. [1] NVP-AEW541 (50 mg/kg) causes tumor shrinkage in both HTLA-230 and SK-N-BE2c xenografts, without signs of systemic toxicity. NVP-AEW541 could inhibit tumor invasion both in Matrigel-coated chambers and in HTLA-230 xenografts. [3]
Clinical Trials
Features
Protocol
Kinase Assay [1]
In vitro kinase assays NVP-AEW541 is dissolved in DMSO (10 mM) and stored at -20 °C. Dilutions are freshly made in DMSO/water 1:1. The final concentration of DMSO in the enzyme assays is <0.5 %.="" the="" protein="" kinase="" assays="" are="" carried="" out="" in="" 96-well="" plates="" at="" rt="" and="" terminated="" by="" the="" addition="" of="" 20="" μl="" of="" 125="" mm="" edta.="" subsequently,="" 30="" μl="" (c-abl,="" c-src,="" igf-1r)="" of="" the="" reaction="" mixture="" are="" transferred="" onto="" immobilon-pvdf="" presoaked="" for="" 5="" min="" with="" methanol,="" rinsed="" with="" water,="" then="" soaked="" for="" 5="" min="" with="" 0.5="" %="">3PO4 and mounted on vacuum manifold. After spotting all samples, vacuum is connected and each well rinsed with 200 μL 0.5 % H3PO4. Membranes are removed and washed 4× on a shaker with 1.0 % H3PO4, once with ethanol. After drying, mounting in Packard TopCount 96-well frame, and adding of 10 μL/well of Microscint, membranes are counted. IC50 values are calculated by linear regression analysis of the percentage inhibition of NVP-AEW541 in duplicate, at four concentrations (usually 0.01, 0.1, 1, and 10 μM). One unit of protein kinase activity is defined as 1 nmol of 33P transferred from [γ33P]ATP to the substrate protein per minute per mg of protein at 37 °C.
Cell Assay [1]
Cell Lines MCF-7 cells
Concentrations ~ 10 μM
Incubation Time 72 hours
Methods Between 3 × 103 and 6 × 103 cells/well are seeded in 96-well plates with a total media volume of 100 μL/well. Increasing concentrations of NVP-AEW541 is added 24 hours thereafter in quadruplicate. 72 hours later, cells are fixed by addition of 25 μL/well Glutaraldehyde (20%) and incubation for 10 min at RT. Cells are then washed 2× with 200 μL/well H2O and 100 μL Methylene Blue (0.05%) is added. After incubation for 10 min at RT, cells are washed 3× with 200 μL/well H2O. 200 μL/well HCl (3%) is added, and following incubation for 30 min at RT on a plate shaker, absorbance is measured at 650 nm.
Animal Study [1]
Animal Models Female Harlan athymic nude mice weighing 18-25 g with NWT-21 cells
Formulation Dissolved in 25 mM L(+)-tartaric acid
Doses 20, 30, or 50 mg/kg
Administration Administered via p.o. twice daily
References
[1] García-Echeverría C, et al. Cancer Cell. 2004, 5(3), 231-239.
[2] Scotlandi K, et al. Cancer Res, 2005, 65(9), 3868-3876.
[3] Tanno B, et al. Clin Cancer Res. 2006, 12(22), 6772-6780.
[4] Gariboldi MB, et al. Biochem Pharmacol, 2010, 80(4), 455-462.
[5] Isebaert SF, et al. Int J Radiat Oncol Biol Phys, 2011, 81(1), 239-247.

专利

专利

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