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LY335979 (Zosuquidar 3HCL)

现货
Catalog No.
A8549
Pgb(P糖蛋白)抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 900.00
现货
10mg
¥ 880.00
现货
50mg
¥ 3,520.00
现货
100mg
¥ 6,160.00
现货

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Background

LY335979 is a selective inhibitor of P-Gp with IC50 value of 1.2 nM [1, 2].

P-gp (P-glycoprotein) is a member of ATP-binding cassette (ABC) transporters and plays a pivotal role in pumping many foreign substances out of cells. It has been reported that abnormal expression of P-Gp is correlated with the multidrug resistance of tumor cells [3].

LY335979 is a potent P-Gp inhibitor and has a different selectivity with the reported P-Gp inhibitor cyclosporin A or verapamil. In drug-resistant cell line HL60/VCR with highly expression of P-Gp, LY335979 exhibited highly restore ability of P-Gp than cyclosporin A or verapamil and the IC 50 value of 1.2 nM [1]. When tested with a panel of cell lines over-expressed P-Gp (CEM/VLB100, MCF-7/ADR, 2780AD, P388/ADR, and UCLA-P3.003VLB), administration of LY335979 reversed the cells resistance to Vinblastine, Doxorubicin, Btoposide and Taxol by inhibiting P-Gp activity [2].

In female nude mice model with UCLA-P3.003VLB MDR tumor cells subcutaneous xenograft, pre-treated with LY335979 (30mg/kg) restored tumor cells sensitivity to Taxol (20 mg/kg) which combination markedly suppressed solid tumor growth compared with control group [2].

References:
1.  Green, L.J., P. Marder, and C.A. Slapak, Modulation by LY335979 of P-glycoprotein function in multidrug-resistant cell lines and human natural killer cells. Biochem Pharmacol, 2001. 61(11): p. 1393-9.
2.  Dantzig, A.H., et al., Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res, 1996. 56(18): p. 4171-9.
3.   Hu, T., et al., Reversal of P-glycoprotein (P-gp) mediated multidrug resistance in colon cancer cells by cryptotanshinone and dihydrotanshinone of Salvia miltiorrhiza. Phytomedicine, 2014. 21(11): p. 1264-72.

文献引用

1. Morad SA, Davis TS, et al. "Role of P-glycoprotein inhibitors in ceramide-based therapeutics for treatment of cancer." Biochem Pharmacol. 2017 Apr 15;130:21-33. PMID:28189725

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt637.0
Cas No.167465-36-3
FormulaC32H34Cl3F2N3O2
SynonymsRS 33295-198; Zosuquidar trihydrochloride; LY335979; LY-335979
Solubility≥17.1mg/mL in DMSO
Chemical Name(R)-1-(4-((1aR,6s,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c][7]annulen-6-yl)piperazin-1-yl)-3-(quinolin-5-yloxy)propan-2-ol trihydrochloride
SDFDownload SDF
Canonical SMILESFC1([C@H](C2=CC=CC=C23)[C@@H]1C4=CC=CC=C4[C@H]3N5CCN(C[C@H](COC6=C7C(N=CC=C7)=CC=C6)O)CC5)F.Cl.Cl.Cl
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

ATP酶实验

通过测定从ATP中释放的无机磷酸而测定P-gp ATP酶活性。于96孔板中,实验在37°C下进行90分钟。在有或无1 mM钒酸钠存在的情况下,膜蛋白((8 ~ 10 μg蛋白)于100 μL缓冲液A(含5 mM叠氮化钠,1 mM乌本苷,1 mM EGTA,3 mM ATP以及由5 mM磷酸烯醇式丙酮酸和3.6 units/mL丙酮酸激酶组成的ATP再生系统)中孵育。Pgp-ATP酶活性定义为总ATP酶活性中对钒酸盐敏感的部分。加入检测液后3分钟读数。使用微孔读数器,在690 nm处测定吸光值。使用磷酸标准曲线测定生成的磷酸 (μmol)。每组样品重复测量3次。

细胞实验 [1]:

细胞系

CEM/VLB100、MCF-7/ADR、2780AD、P388/ADR和UCLA-P3.003VLB细胞

制备方法

在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

0.1 ~ 2 μM

实验结果

LY335979是一种有效的调节剂,在0.1 ~ 2 μM的浓度下最大效应地逆转耐药细胞对各种抗癌药物(Vinblastine、Doxorubicin、Btoposide和Taxol)的敏感性。在0.05 μM的浓度下,LY335979的调节剂活性减少了约50%。

动物实验 [1]:

动物模型

携带UCLA-P3.003VLB肿瘤细胞的裸鼠

给药剂量

30 mg/kg;腹腔注射

实验结果

在表达Pgp的人非小细胞肺癌异种移植模型中,20 mg/kg Taxol和30 mg/kg LY335979联合用药在第12天和第19天显著抑制实体瘤生长。此外,没有观察到体重减轻 。

其它注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Dantzig, A.H., et al., Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res, 1996. 56(18): p. 4171-9.

生物活性

Description Zosuquidar(LY335979)是P-糖蛋白介导的多药耐药性的强效调节剂。Ki值为60 nM。
靶点 P-gp          
IC50 60 nM(Ki)          

质量控制

化学结构

LY335979(Zosuquidar 3HCI)

相关生物数据

LY335979(Zosuquidar 3HCI)