1、Product Data SheetTariquidarCat. No.: HY-10550CAS No.: 206873-63-4分式: CHNO分量: 646.73作靶點(diǎn): P-glycoprotein作通路: Membrane Transporter/Ion Channel儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 2.5 mg/mL (3.87 mM; Need ultrasonic)H2O : 0.1 mg/mL (insoluble)SolventMas

2、s1 mg 5 mg 10 mgConcentration制備儲(chǔ)備液1 mM 1.5462 mL 7.7312 mL 15.4624 mL5 mM 10 mM 請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲(chǔ)備液；旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?6 個(gè)內(nèi)使，-20C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?1 個(gè)內(nèi)使。體內(nèi)實(shí)驗(yàn) 1. Tariquidar is dissolved in DMSO and adding heated 5% glucose solution (w/v) to a

3、final DMSO concentration 2.3.2% (v/v)5.Tariquidar (4 mg/mL) solution is prepared by adding it to a 5% DMSO-5% glucose solution3.Tariquidar is freshly prepared on each experimental day in 2.5% aqueous dextrose solution4.BIOLOGICAL ACTIVITY物活性 Tariquidar種有效的特異性P-glycoprotein (P-gp)抑制劑，Kd 為 5.10.9 nM。I

4、C & Target Kd: 5.1 nM (P-gp)1體外研究Tariquidar (XR9576) is a potent modulator of P-gp mediated 3H-Vinblastine and 3H-Paclitaxel transport as itincreases the steady-state accumulation of these cytotoxics in CHrB30 cells to levels observed in non-P-gp-expressingPage 1 of 2 www.MedChemEAuxB1 cells (EC50=4

5、8750 nM). 3H-Tariquidar binds to CHrB30 membranes with the highest affinity (Kd=5.10.9 nM,n=7) and a binding capacity (Bmax) of 27515 pmol/mg membrane protein. In contrast to the parental cell line, theaccumulation of 3H-Vinblastine is increased in a dose-dependent fashion by the modulators Tariquid

6、ar (EC50=48750 nM). The MDR modulator Tariquidar is able to inhibit 60-70% of the vanadate-sensitive ATPase activity, withpotent IC50 value of 439 nM1. Tariquidar (XR9576) potentiates the cytotoxicity of several drugs includingDoxorubicin, Paclitaxel, Etoposide, and Vincristine; complete reversal of

7、 resistance is achieved in the presence of 25-80 nM XR9576. Tariquidar is a potent inhibitor of photoaffinity labeling of P-gp by 3HAzidopine implying a directinteraction with the protein2.體內(nèi)研究 In mice bearing the intrinsically resistant MC26 colon tumors, coadministration of Tariquidar (XR9576) pot

8、entiates theantitumor activity of Doxorubicin without a significant increase in toxicity; maximum potentiation is observed at 2.5-4.0 mg/kg dosed either i.v. or p.o. In addition, coadministration of Tariquidar (6-12 mg/kg p.o.) fully restores theantitumor activity of Paclitaxel, Etoposide, and Vincr

9、istine against two highly resistant MDR human tumor xenografts(2780AD, H69/LX4) in nude mice. Tariquidar is found to also significantly potentiate the antitumor activity ofdoxorubicin against s.c. MC26 tumors in vivo2.PROTOCOLCell Assay 2 Cells (EMT6 AR1.0 8102/well; A2780 5103/well; 2780AD 6103/wel

10、l) are seeded into 96-well plates. After 4 h,varying concentrations of Tariquidar are added, and cells are incubated for an additional 4 days (EMT6 AR1.0) or 6days (2780AD) before quantification of cell growth and calculation of IC10 values (concentration resulting in 10%inhibition of cell growth)2.

11、MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice2Administration 2 MC26 tumor slurry is implanted s.c. in BALB/c mice (day 0). The animals are then randomized, 24 h later, into groupsof 15-18 and treated once with various regimens. Tariquidar

12、or vehicle is administered either i.v. via a lateral tail veinor p.o. with Doxorubicin (5 mg/kg) or vehicle i.v. The modulator is administered either i.v. at 2-4 mg/kg (10 mL/kg) atthe same time as Doxorubicin or p.o. at 2-8 mg/kg (10 mL/kg) 1 h before the Cytotoxic drug. GG918 is administeredp.o. 1

13、 h before doxorubicin. All of the animals are weighed twice weekly. The animals are killed by cervical dislocationon day 14, and the tumors are excised and weighed. The data are analyzed by Students t test.Rats2Male CD rats (3 animals per time point) are dosed i.v. with paclitaxel alone 15 min infus

14、ion at 10 mg/kg in Tween80:ethanol:5% dextrose (5:10:85% v/v/v) or in combination with Tariquidar (10 mg/kg). Tariquidar is administered asa bolus (i.v.) dose 15 min before infusion of Paclitaxel. Blood samples are collected by cardiac puncture usingheparinized syringes at various times between 0.08

15、3 and 48 h and are centrifuged to prepare plasma, which is storedat 20C until analysis. Paclitaxel concentration in plasma samples is measured by a LC-MS/MS assay.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Sci Bull. 2016 Apr;61(7):552-5

16、60. J Cereb Blood Flow Metab. 2018 Oct 24:271678X18806640. J Cereb Blood Flow Metab. 2016 Aug;36(8):1412-23. J Biomed Nanotechnol. 2018 Oct 1;14(10):1705-1718. Eur J Med Chem. 2018 Mar 10;147:7-20.Page 2 of 3 www.MedChemESee more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1

17、. Martin C, et al. The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br J Pharmacol, 1999, 128(2), 403-411.2. Mistry P, et al. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res, 2001,6

18、1(2), 749-758.3. Zimmermann ES, et al. Simultaneous Semimechanistic Population Analyses of Levofloxacin in Plasma, Lung, and Prostate To Describe the Influence ofEfflux Transporters on Drug Distribution following Intravenous and Intratracheal Administration. Antimicrob Agents Chemother. 2015 Nov 30;60(2):946-54.4. Kao YH, et al. Regulation of P-glycoprotein expre