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MedKoo Cat#: 201065 | Name: Dofequidar
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Dofequidar, also known as MS-209, is a quinolone-derived sphingomyelin synthase inhibitor that blocks P-glycoprotein and multidrug resistance-associated protein-1, is under development by Schering for the potential treatment of multidrug resistant tumors. Dofequidar was found to sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export.

Chemical Structure

Dofequidar
Dofequidar
CAS#129716-58-1 (free base)

Theoretical Analysis

MedKoo Cat#: 201065

Name: Dofequidar

CAS#: 129716-58-1 (free base)

Chemical Formula: C30H31N3O3

Exact Mass: 481.2365

Molecular Weight: 481.59

Elemental Analysis: C, 74.82; H, 6.49; N, 8.73; O, 9.97

Price and Availability

Size Price Availability Quantity
5mg USD 120.00 Ready to ship
10mg USD 190.00 Ready to ship
25mg USD 350.00 Ready to ship
50mg USD 550.00 Ready to ship
100mg USD 850.00 Ready to ship
200mg USD 1,250.00 Ready to ship
500mg USD 2,150.00 Ready to ship
1g USD 3,450.00 Ready to ship
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Related CAS #
129716-58-1 (free base) 153653-30-6 (furamate 1:1) 158681-49-3 (furamate 1:1.5)
Synonym
MS-209; MS 209; MS209; Dofequidar
IUPAC/Chemical Name
1-(4-(2-hydroxy-3-(quinolin-5-yloxy)propyl)piperazin-1-yl)-2,2-diphenylethanone
InChi Key
KLWUUPVJTLHYIM-UHFFFAOYSA-N
InChi Code
InChI=1S/C30H31N3O3/c34-25(22-36-28-15-7-14-27-26(28)13-8-16-31-27)21-32-17-19-33(20-18-32)30(35)29(23-9-3-1-4-10-23)24-11-5-2-6-12-24/h1-16,25,29,34H,17-22H2
SMILES Code
OC(COC1=C2C=CC=NC2=CC=C1)CN3CCN(C(C(C4=CC=CC=C4)C5=CC=CC=C5)=O)CC3
Appearance
white solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
A substance that is being studied for its ability to make cancer cells respond better to chemotherapy drugs to which they have become resistant. It belongs to the family of drugs called quinolone antibiotics. A synthetic quinoline derivative with multidrug resistance (MDR) modulating properties. Dofequidar fumarate, like many other MDR reversal agents, binds competitively to the drug-binding site of the transmembrane P-glycoprotein efflux pump (P-gp). Once bound to the P-gp efflux pump, dofequidar is transported out of transformed cells by a mechanism similar to that used by cytotoxic drugs, thereby blocking the efflux of these compounds from the cell. Inhibition of the efflux pump by this agent leads to a retention of the cytotoxic drug resulting in increased intracellular drug concentrations, thereby enhancing cytotoxicity. Dofequidar has demonstrated reversal of the MDR phenotype in those cells exposed to various chemotherapeutic agents, such as vinca alkaloids and anthracyclines.      
Biological target:
Dofequidar(MS-209) is a novel quinoline compound, which can reverse P-glycoprotein (P-gp)-mediated MDR.
In vitro activity:
Because dofequidar could reduce the cell number in the SP fraction that highly expressed ABCG2/BCRP (Figs 3,4), it was hypothesized that dofequidar had the ability to inhibit ABCG2/BCRP in addition to the previously reported ABCB1/P-gp and ABCC1/MRP1. Parental K562 cells or K562 stable transfectants were stained with Hoechst33342 in the presence or absence of ABC-T inhibitors. Dofequidar but not verapamil could increase the intracellular Hoechst33342 concentration in K562/BCRP cells dose dependently (Fig. S1B). Similar results were obtained in KB/BCRP cells (data not shown). To confirm the result, this study carried out an in vitro vesicle transport assay. Membrane vesicles from control or ABCG2/BCRP-overexpressing insect cells were incubated with [3H]MTX in the presence of ATP or AMP. The ATP-dependent uptake of [3H]MTX was observed in ABCG2/BCRP-overexpressing membrane vesicles but not in control vesicles (Fig. 4A). FTC (Fumitremorgin C) and dofequidar, but not verapamil, inhibited [3H]MTX uptake dose dependently (Fig. 5A). These results suggest that dofequidar had the ability to inhibit ABCG2/BCRP in addition to the previously reported ABCB1/P-gp and ABCC1/MRP1. Reference: Cancer Sci. 2009 Nov;100(11):2060-8. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1349-7006.2009.01288.x
In vivo activity:
FTC is not suitable for clinical studies because of its severe toxicity, but it strongly and specifically inhibits ABCG2/BCRP. On the other hand, dofequidar exhibits low toxicity and has already been approved for clinical trials. To overcome the chemoresistance of cancer stem-like SP cells in vivo, this study evaluated the antitumor activity of CPT-11 plus dofequidar in a clinically relevant model. HeLa-derived SP and NSP cells were transplanted into nude mice, and the xenografted tumors were treated with CPT-11 with or without dofequidar. Dofequidar (200 mg/kg) was orally administrated 30 min before CPT-11 (67 mg/kg) injection. Although xenografted HeLa SP cells showed resistance to CPT-11, co-treatment of the mice with dofequidar drastically decreased the tumor volume (Fig. 6B, left panel), like that seen in CPT-11-treated or CPT-11 plus dofequidar-treated NSP-bearing mice (Fig. 6B, right panel). Dofequidar alone had almost no effect on SP- or NSP-derived tumor growth in vivo. To assess the toxicity, the study measured the bodyweight of the tumor-bearing mice. The mice seemed to be healthy (Fig. 6C), and the change in bodyweight was very small (data not shown). Thus CPT-11 plus dofequidar therapy appeared to have good therapeutic efficacy in vivo by sensitizing cancer stem-like cells to anticancer drugs. Reference: Cancer Sci. 2009 Nov;100(11):2060-8. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1349-7006.2009.01288.x

Preparing Stock Solutions

The following data is based on the product molecular weight 481.59 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N. Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Cancer Sci. 2009 Nov;100(11):2060-8. doi: 10.1111/j.1349-7006.2009.01288.x. Epub 2009 Jul 17. PMID: 19673889.
In vitro protocol:
1. Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N. Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Cancer Sci. 2009 Nov;100(11):2060-8. doi: 10.1111/j.1349-7006.2009.01288.x. Epub 2009 Jul 17. PMID: 19673889.
In vivo protocol:
1. Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N. Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Cancer Sci. 2009 Nov;100(11):2060-8. doi: 10.1111/j.1349-7006.2009.01288.x. Epub 2009 Jul 17. PMID: 19673889.
1: Saeki T, Nomizu T, Toi M, Ito Y, Noguchi S, Kobayashi T, Asaga T, Minami H, Yamamoto N, Aogi K, Ikeda T, Ohashi Y, Sato W, Tsuruo T. Dofequidar fumarate (MS-209) in combination with cyclophosphamide, doxorubicin, and fluorouracil for patients with advanced or recurrent breast cancer. J Clin Oncol. 2007 Feb 1;25(4):411-7. doi: 10.1200/JCO.2006.08.1646. Epub 2006 Dec 18. PMID: 17179098. 2: Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N. Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Cancer Sci. 2009 Nov;100(11):2060-8. doi: 10.1111/j.1349-7006.2009.01288.x. Epub 2009 Jul 17. PMID: 19673889. 3: Robert J. MS-209 Schering. Curr Opin Investig Drugs. 2004 Dec;5(12):1340-7. PMID: 15648956. 4: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. PMID: 17805439. 5: Tsuruo T, Tomida A. Multidrug resistance. Anticancer Drugs. 1995 Apr;6(2):213-8. doi: 10.1097/00001813-199504000-00003. PMID: 7795269. 6: Wu M, Li T, Chen L, Peng S, Liao W, Bai R, Zhao X, Yang H, Wu C, Zeng H, Liu Y. Essential oils from Inula japonica and Angelicae dahuricae enhance sensitivity of MCF-7/ADR breast cancer cells to doxorubicin via multiple mechanisms. J Ethnopharmacol. 2016 Mar 2;180:18-27. doi: 10.1016/j.jep.2016.01.015. Epub 2016 Jan 18. PMID: 26795076. 7: Naito M, Tsuruo T. Therapeutic approach to drug resistant tumors. Ther Drug Monit. 1998 Oct;20(5):577-80. doi: 10.1097/00007691-199810000-00022. PMID: 9780138. 8: Saeki T, Tsuruo T, Sato W, Nishikawsa K. Drug resistance in chemotherapy for breast cancer. Cancer Chemother Pharmacol. 2005 Nov;56 Suppl 1:84-9. doi: 10.1007/s00280-005-0106-4. PMID: 16273361. 9: Tsuruo T. [MDR reversing drugs for clinical development]. Gan To Kagaku Ryoho. 1994 Jun;21(7):962-7. Japanese. PMID: 8002634. 10: Kortylewicz ZP, Augustine AM, Nearman J, McGarry J, Baranowska-Kortylewicz J. Radioiodinated agents for imaging multidrug resistant tumors. Med Chem. 2009 Mar;5(2):171-81. doi: 10.2174/157340609787582954. PMID: 19275716. 11: Takeshita A, Ohno R. [New combination therapies in hematological malignancies]. Gan To Kagaku Ryoho. 2000 Mar;27(3):388-94. Japanese. PMID: 10740632. 12: Naito M, Nakanishi O, Tsuruo T. [Overcoming of multidrug resistance by a newly synthesized quinoline compound, MS-209]. Nihon Rinsho. 1997 May;55(5):1122-7. Japanese. PMID: 9155163. 13: Suzuki T, Mabuchi K, Fukazawa N. Synthesis of glucuronides of multidrug resistance reversing drug MS-209. Bioorg Med Chem Lett. 1999 Mar 8;9(5):659-62. doi: 10.1016/s0960-894x(99)00056-6. PMID: 10201824. 14: Nonomiya Y, Noguchi K, Tanaka N, Kasagaki T, Katayama K, Sugimoto Y. Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells. Cancer Sci. 2016 Dec;107(12):1877-1887. doi: 10.1111/cas.13093. Epub 2016 Dec 19. PMID: 27699933; PMCID: PMC5198950. 15: Baba M, Nakanishi O, Sato W, Saito A, Miyama Y, Yano O, Shimada S, Fukazawa N, Naito M, Tsuruo T. Relationship between multidrug resistant gene expression and multidrug resistant-reversing effect of MS-209 in various tumor cells. Cancer Chemother Pharmacol. 1995;36(5):361-7. doi: 10.1007/BF00686183. PMID: 7634376. 16: Sato W, Fukazawa N, Nakanishi O, Baba M, Suzuki T, Yano O, Naito M, Tsuruo T. Reversal of multidrug resistance by a novel quinoline derivative, MS-209. Cancer Chemother Pharmacol. 1995;35(4):271-7. doi: 10.1007/BF00689444. PMID: 7828268. 17: Suzuki T, Fukazawa N, San-nohe K, Sato W, Yano O, Tsuruo T. Structure- activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer. J Med Chem. 1997 Jun 20;40(13):2047-52. doi: 10.1021/jm960869l. PMID: 9207946. 18: Sasajima T, Shimada N, Naitoh Y, Takahashi M, Hu Y, Satoh T, Mizoi K. (99m)Tc-MIBI imaging for prediction of therapeutic effects of second-generation MDR1 inhibitors in malignant brain tumors. Int J Cancer. 2007 Dec 15;121(12):2637-45. doi: 10.1002/ijc.23011. PMID: 17708555. 19: Nakamura T, Oka M, Aizawa K, Soda H, Fukuda M, Terashi K, Ikeda K, Mizuta Y, Noguchi Y, Kimura Y, Tsuruo T, Kohno S. Direct interaction between a quinoline derivative, MS-209, and multidrug resistance protein (MRP) in human gastric cancer cells. Biochem Biophys Res Commun. 1999 Feb 24;255(3):618-24. doi: 10.1006/bbrc.1999.0245. PMID: 10049760. 20: Diéras V, Bonneterre J, Laurence V, Degardin M, Pierga JY, Bonneterre ME, Marreaud S, Lacombe D, Fumoleau P. Phase I combining a P-glycoprotein inhibitor, MS209, in combination with docetaxel in patients with advanced malignancies. Clin Cancer Res. 2005 Sep 1;11(17):6256-60. doi: 10.1158/1078-0432.CCR-04-2316. PMID: 16144929.