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336113-53-2 分子结构
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N-(3-aminopropyl)-N-[(1R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl]-4-methylbenzamide

ChemBase编号:72685
分子式:C30H33ClN4O2
平均质量:517.06162
单一同位素质量:516.229204
SMILES和InChIs

SMILES:
c1cc(ccc1)Cn1c(=O)c2c(nc1[C@H](N(CCCN)C(=O)c1ccc(cc1)C)C(C)C)cc(cc2)Cl
Canonical SMILES:
NCCCN([C@@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)C(=O)c1ccc(cc1)C
InChI:
InChI=1S/C30H33ClN4O2/c1-20(2)27(34(17-7-16-32)29(36)23-12-10-21(3)11-13-23)28-33-26-18-24(31)14-15-25(26)30(37)35(28)19-22-8-5-4-6-9-22/h4-6,8-15,18,20,27H,7,16-17,19,32H2,1-3H3/t27-/m1/s1
InChIKey:
QJZRFPJCWMNVAV-HHHXNRCGSA-N

引用这个纪录

CBID:72685 http://www.chembase.cn/molecule-72685.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
N-(3-aminopropyl)-N-[(1R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl]-4-methylbenzamide
IUPAC传统名
ispinesib
别名
SB-715992
CK0238273
Ispinesib mesilate(SB-715992)
N-(3-Aminopropyl)-N-[(1R)-1-[7-chloro-3,4-dihydro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]-2-methylpropyl]-4-methylbenzamide
SB 715992
Ispinesib
CAS号
336113-53-2
PubChem SID
162037606
PubChem CID
6851740

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
PubChem 6851740 external link

理论计算性质

理论计算性质

JChem
Acid pKa 19.677425  质子受体
质子供体 LogD (pH = 5.5) 2.5223167 
LogD (pH = 7.4) 3.2466588  Log P 5.5308585 
摩尔折射率 151.4206 cm3 极化性 56.890957 Å3
极化表面积 79.0 Å2 可自由旋转的化学键
里宾斯基五规则 false 

分子性质

分子性质

理化性质 安全信息 药理学性质 产品相关信息 生物活性(PubChem)
溶解度
DMSO expand 查看数据来源
保存条件
-20°C expand 查看数据来源
MSDS下载
下载链接 expand 查看数据来源
作用靶点
Ksp expand 查看数据来源
成盐信息
Free Base expand 查看数据来源
质检报告
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详细说明

详细说明

Selleck Chemicals Selleck Chemicals TRC TRC
Selleck Chemicals -  S1452 external link
Research Area
Description Cancer
Biological Activity
Description Ispinesib (SB-715992, CK0238273) is a potent, specific and reversible inhibitor of KSP (HsEg5) with Ki of 1.7 nM.
Targets KSP (HsEg5)
IC50 1.7 nM (Ki app) [
In Vitro Ispinesib is a potent, allosteric, reversible, and specific inhibitor of KSP, which changes the binding property of KSP to microtubules and disturbs its movement by inhibiting ADP release without altering the release of the KSP-ADP complex from the microtubule. [1]Ispinesib shows potent cytotoxic activity in a panel of tumor cell lines, including Colo205, Colo201, HT-29, M5076, Madison-109, and MX-1, with IC50 of 1.2 nM to 9.5 nM. [2]In PC-3 prostate cancer cells, Ispinesib (15 nM and 30 nM) blocks cell proliferation and induces apoptosis by regulating the expression levels of genes that controls apoptosis, cell proliferation, cell cycle, and cell signaling, such as EFGR, p27, p15, and IL-11. [3]In a panel of 53 breast cell lines, Ispinesib (7.4 nM–600 nM) demonstrates broad inhibitory activity. In BT-474 and MDA-MB-468 cells, Ispinesib (150 nM) induces apoptosis, as revealed by a higher proportion of apoptotic cells, lower antiapoptotic Bcl-XL level, and higher proapoptotic Bax and Bid levels. [4]
In Vivo Ispinesib (4.5 mg/kg–15 mg/kg) exhibits inhibitory effects against Colo205, Colo201, HT-29, but not MX-1 cells, in mouse xenograft models. SB-715992 (6 mg/kg–10 mg/kg ) also inhibits murine solid tumors, including Madison 109 lung carcinoma, M5076 sarcoma, as well as L1210 and P388 leukemias. [2]In mice xenograft models of breast cancer cells MCF-7, HCC1954, MDA-MB-468, and KPL4, Ispinesib (8 mg/kg–10 mg/kg) inhibits tumor growth. [4]
Clinical Trials Investigations of Ispinesib in multiple Phase II clinical trials for several cancers, including kidney, prostate, colorectal, liver, ovarian, and breast cancers, have been completed.
Features Ispinesib (SB-715992) is an allosteric, potent, specific, and reversible inhibitor of the mitotic kinesin spindle protein (KSP) (HsEg5).
Protocol
Kinase Assay [1]
Steady-State Kinetic Analysis of Human KSP ATPase Activity and Inhibition by Ispinesib Kinesin specificity analysis is carried out using a pyruvate kinase-lactate dehydrogenase detection system that couples the production of ADP to oxidation of NADH. Absorbance changes are monitored at 340 nm. Steady-state studies using nanomolar concentrations of KSP are performed using a sensitive fluorescence-based assay utilizing a pyruvate kinase, pyruvate oxidase, and horseradish peroxidase (HRP) coupled detection system that couples the generation of ADP to oxidation of Amplex Red to fluorescent resorufin. Generation of resorufin is monitored by fluorescence (λexcitation = 520 nm and λemission = 580 nm). Steady-state biochemical experiments are performed in PEM25 buffer [25 mM Pipes-K+ (pH 6.8), 2 mM MgCl2, 1 mM EGTA] supplemented with 10 μM paclitaxel for experiments involving microtubules. The IC50 for steady-state inhibition is determined at 500 μM ATP, 5 μM Microtubules, and 1 nM KSP in PEM25 buffer. Ki app (apparent inhibitor dissociation constant) values of Ispinesib are extracted from the dose-response curves, with explicit correction for enzyme concentration by using the Morrison equation.Inhibitor modality (e.g., competitive, noncompetitive, uncompetitive, or mixed) under steady-state conditions is determined by measuring the effect of inhibitor concentration on initial velocity as a function of substrate concentrations. Data are fit using equations in GraFit to velocity equations for the various modes of inhibition.
Cell Assay [4]
Cell Lines Breast cancer cells, including MCF-7, HCC1954, MDA-MB-468, and KPL4
Concentrations 0.085 nM–33 μM
Incubation Time 72 hours
Methods Cells are plated in log phase of growth in 96-well plates and treated with Ispinesib for 72 hours. Then, cell growth is measured using CellTiter-Glo, and luminescence is detected using BioTek FLx800. Data are analyzed and the IC50 value, defined as the drug concentration that results in 50% growth inhibition relative to control, is calculated.
Animal Study [4]
Animal Models Nude (nu/nu) mice models of MCF7, KPL4, and HCC1954 cells; severe combined immunodeficient (SCID) mice model of MDA-MB-468 cells;
Formulation Dissolved in 10% ethanol, 10% cremophor, and 80% D5W (dextrose 5%)
Doses 10 mg/kg for nude mice or 8 mg/kg for SCID mice
Administration Intraperitoneal injection on a q4d×3 schedule (3 doses, every 4 days)
References
[1] Lad L, et al. Biochemistry, 2008, 47(11), 3576-3585.
[2] Johnson RK, et al. Proc Am Assoc Cancer Res, 2002, 43, 269.
[3] Davis DA, et al. BMC Cancer, 2006, 6, 22.
[4] Purcell JW, et al. Clin Cancer Res, 2010, 16(2), 566-576.
Toronto Research Chemicals -  I918500 external link
Ispinesib is the first potent, highly specific small-molecule inhibitor of KSP tested for the treatment of human disease. Anticancer agent.

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参考文献

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