- Tariquidar methanesulfonate, hydrate
- Tariquidar
- LY335979 (Zosuquidar 3HCL)
- Dofequidar fumarate
ZosuquidarMDR modulator |
Sample solution is provided at 25 µL, 10mM.
Quality Control & MSDS
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- Purity = 98.49%
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- MSDS (Material Safety Data Sheet)
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Chemical structure
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Cas No. | 167354-41-8 | SDF | Download SDF |
Synonyms | LY335979;LY 335979;LY-335979 | ||
Chemical Name | (2R)-1-(4-((1aR,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 | ||
Canonical SMILES | FC1([C@@](C2=C([H])C([H])=C([H])C([H])=C23)([H])[C@]1([H])C4=C([H])C([H])=C([H])C([H])=C4C3([H])N5C([H])([H])C([H])([H])N(C([H])([H])[C@@](C([H])([H])OC6=C([H])C([H])=C([H])C7=C6C([H])=C([H])C([H])=N7)([H])O[H])C([H])([H])C5([H])[H])F | ||
Formula | C32H31F2N3O2 | M.Wt | 527.6 |
Solubility | Soluble in DMSO | Storage | Store at -20°C |
Shipping Condition | Evaluation sample solution : ship with blue ice.All other available size:ship with RT , or blue ice upon request | ||
General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. |
Zosuquidar (LY335979) 3HCl is a novel and potent modulator of P-glycoprotein (P-gp) [1]. P-gp is wildly expressed in brain, liver, small intestine and tumor cells and acts as an efflux pump responsible for multidrug resistance in tumor cells. Overexpression of Pgp in tumors results in multidrug resistance (MDR) to structurally unrelated oncolytics [2].
In vitro: In CEM/VLB100 cells, LY335979 treatment (0.1 μM) fully restored the sensitivity to vinblastine, doxorubicin (Dox), etoposide, and Taxol. In CEM/VLB100 plasma membranes, LY335979 blocked [3H]azidopinephotoaffinity labeling of the M(r) approximately 170,000 Pgp and competitively inhibited equilibrium binding of [3H]vinblastine to Pgp with the Ki value of approximately 0.06 μM [3]. In all P-gp-expressing leukemia cell linesincluding K562/HHT40, K562/HHT90, K562/DOX and HL60/DNR, Zosuquidar completely or partially restored drug sensitivity. In primary AML blasts with active P-gp, Zosuquidar enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumabozogamicin (Mylotarg)[4].
In vivo: In mice bearing P388/ADR murine leukemia cells,treatment with LY335979 in combination with Dox or etoposide significantly increased in life span with no apparent alteration of pharmacokinetics. In a MDR human non-small cell lung carcinoma nude mouse xenograft model, LY335979 enhanced the antitumor activity of Taxol [3].
Clinical trials: In patients with untreated non-Hodgkin"s lymphoma,a phase I/II trial was conducted to investigate the safety and tolerance of zosuquidar. In patients giving three doses of 500 mg of zosuquidar p.o. in combination with CHOX, toxicity was minimal and no enhancement of CHOP-related toxicity was observed [5]. In patients with advanced solid tumours in Phase I study, zosuquidar(100–300 mg/m2) can inhibit vinorelbine clearance to a modest degree[6].
References:[1] Cripe L D, Uno H, Paietta E M, et al. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999[J]. Blood, 2010, 116(20): 4077-4085.[2] Chaudhary P M, Roninson I B. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells[J]. Cell, 1991, 66(1): 85-94.[3] Dantzig A H, Shepard R L, Cao J, et al. Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979[J]. Cancer Research, 1996, 56(18): 4171-4179.[3] Tang R, Faussat A M, Perrot J Y, et al. Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML)[J]. BMC cancer, 2008, 8(1): 1.[4] Morschhauser F, Zinzani P L, Burgess M, et al. Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar. 3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin"s lymphoma[J]. Leukemia & lymphoma, 2007, 48(4): 708-715.[5] Lê L H, Moore M J, Siu L L, et al. Phase I study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours[J]. Cancer chemotherapy and pharmacology, 2005, 56(2): 154-160.
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《血管紧张素转换酶抑制剂在心血管病中应用的中国专家共识》.PDF(242.69k)
1、测定酶比活力:底物需要过量么?测定时间多长?是否可以加入过量的底物,然后测定3min吸光度的增加值,从吸光度的变化值计算比活力。
2、在酶抑制剂筛选的过程中,是否需要保证底物过量?还是要水浴一定时间让反应完全?我看到文献说用终浓度为0.1μmol/mL的底物,终浓度为45U/ml的酶,我想问,假设总体积为1ml,那么终浓度为45U/ml的酶岂不是每分钟能转化4.8μmol的底物?那么0.1μmol/mL的底物不就几秒钟就反应完了?那么怎么测定初速度?
1.对于抑制剂筛选工作(求ic50)是不是体系内酶与底物的量(底物应该是过量的)对实验结果影响不大。
2.如果要求算Km值,是不是需要知道反应产物的绝对量。反应时间文献上都是5分钟,反应速度就用反应产物量除以反应时间即可。
3.酶是进口分装的,规格5U,一次用不完,用PBS稀释后如何保存
谢谢
2、可逆抑制剂:包括
a、竞争性抑制剂,抑制剂与底物竞争性结合酶反应中心,使Km增大,而Vmax不变 b、非竞争性抑制剂,酶与抑制剂结合后还能与底物结合,但活性降低,使Vmax减小,而Km不变
c、反竞争性抑制剂,酶只能与底物结合后才能与抑制剂结合,Vmax与Km都减小
可逆抑制剂可用透析等方法除去,使酶恢复作用
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