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Zosuquidar (formerly also known as LY335979) is a novel and potent inhibitor P-glycoprotein (P-gp) and modulator of P-gp-mediated multi-drug resistance with Ki of 60 nM in a cell-free assay. Zosuquidar binds with high affinity to P-glycoprotein and inhibits P-glycoprotein-mediated multidrug resistance (MDR). P-glycoprotein, encoded by the MDR-1 gene, is a member of the ATP-binding cassette superfamily of transmembrane transporters and prevents the intracellular accumulation of many natural product-derived cytotoxic agents.
Physicochemical Properties
| Molecular Formula | C32H31F2N3O2 | |
| Molecular Weight | 527.6 | |
| Exact Mass | 527.238 | |
| CAS # | 167354-41-8 | |
| Related CAS # | Zosuquidar trihydrochloride;167465-36-3 | |
| PubChem CID | 3036703 | |
| Appearance | Off-white to light yellow solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Boiling Point | 690.5±55.0 °C at 760 mmHg | |
| Flash Point | 371.4±31.5 °C | |
| Vapour Pressure | 0.0±2.3 mmHg at 25°C | |
| Index of Refraction | 1.691 | |
| LogP | 4.3 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 39 | |
| Complexity | 806 | |
| Defined Atom Stereocenter Count | 3 | |
| SMILES | C1CN(CCN1C[C@H](COC2=CC=CC3=C2C=CC=N3)O)C4C5=CC=CC=C5[C@H]6[C@H](C6(F)F)C7=CC=CC=C47 |
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| InChi Key | IHOVFYSQUDPMCN-XAKVHENESA-N | |
| InChi Code | InChI=1S/C32H31F2N3O2/c33-32(34)29-22-7-1-3-9-24(22)31(25-10-4-2-8-23(25)30(29)32)37-17-15-36(16-18-37)19-21(38)20-39-28-13-5-12-27-26(28)11-6-14-35-27/h1-14,21,29-31,38H,15-20H2/t21-,29-,30+,31?/m1/s1 | |
| Chemical Name | (2R)-1-[4-[(2R,4S)-3,3-difluoro-11-tetracyclo[10.4.0.02,4.05,10]hexadeca-1(16),5,7,9,12,14-hexaenyl]piperazin-1-yl]-3-quinolin-5-yloxypropan-2-ol | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | In P-glycoprotein-active cell lines, zosuquidar (0.3 μM; 48 h) therapy increases the cytotoxicity of DNR (substrates for P-glycoproteins)[2]. Drug-sensitive and multidrug-resistant cell lines exhibit high cytotoxic concentrations when treated with zosuquidar (5–16 μM) for 72 hours[1]. |
| ln Vivo | Treatment with zosuquidar (intraperitoneal injection; 30, 10, 3, or 1 mg/kg; once daily; 5 d) significantly lengthens life[1]. Doxorubicin combined with Zosuquidar (intraperitoneal injection; 30 mg/kg; once daily; 5 d) treatment demonstrates the potentiation[1]. |
| Cell Assay |
Cell Cytotoxicity Assay[2] Cell Types: K562 and HL60 cells Tested Concentrations: 0.3 μM Incubation Duration: 48 hrs (hours) Experimental Results: Enhanced the cytotoxicity of DNR (substrates for P-glycoproteins) in K562/DOX cells more than 45.5-fold. Cell Cytotoxicity Assay[1] Cell Types: CCRF-CEM, CEM/VLB100, P388, P388/ADR, MCF7, MCF7/ADR, 2780, 2780AD, UCLA-P3, UCLA-P3.003VLB cells Tested Concentrations: 5-16 μM Incubation Duration: 72 hrs (hours) Experimental Results: demonstrated IC50s of 6, 7, 15, 8, 7, 15, 11, 16, >5, >5 μM for CCRF-CEM, CEM/VLB100, P388, P388 /ADR, MCF7, MCF7/ADR, 2780, 2780AD, UCLA-P3, UCLA-P3.003VLB cells, respectively. |
| Animal Protocol |
Animal/Disease Models: Mice implanted with P388/ADR tumors[1] Doses: 30, 10, 3, or 1 mg/kg Route of Administration: intraperitoneal (ip)injection; 30, 10, 3 , or 1 mg/kg; one time/day; 5 days Experimental Results: Exihibited a Dramatically increased survival compared to the group treated with Doxorubicin alone (P<0.001). Animal/Disease Models: Mice implanted with P388 or P388/ADR murine leukemia cells[1] Doses: 30 mg/kg Route of Administration: intraperitoneal (ip)injection; 30 mg/kg; one time/day; 5 days Experimental Results: Observed significant antitumor activity against the MDR P388/ADR cell lines when mice were treated with a combined dose of 30 mg/kg LY335979 and 1 mg/kg Doxorubicin (P=0.1). |
| References |
[1]. Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res. 1996 Sep 15;56(18):4171-9. [2]. Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML). BMC Cancer. 2008 Feb 13;8:51. [3]. 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. Blood. 2010 Nov 18;116(20):4077-85. |
| Additional Infomation |
LSM-5782 is a carbopolycyclic compound. Zosuquidar is a compound of antineoplastic drug candidates currently under development. It is now in "Phase 3" of clinical tests in the United States. Its action mechanism consists of the inhibition of P-glycoproteins; other drugs with this mechanism include tariquidar and laniquidar. Zosuquidar Trihydrochloride is a difluorocyclopropyl quinoline. Zosuquidar trihydrochloride binds with high affinity to P-glycoprotein and inhibits P-glycoprotein-mediated multidrug resistance (MDR). P-glycoprotein, encoded by the MDR-1 gene, is a member of the ATP-binding cassette superfamily of transmembrane transporters and prevents the intracellular accumulation of many natural product-derived cytotoxic agents. (NCI04) Zosuquidar is a difluorocyclopropyl quinoline. Zosuquidar binds with high affinity to P-glycoprotein and inhibits P-glycoprotein-mediated multidrug resistance (MDR). P-glycoprotein, encoded by the MDR-1 gene, is a member of the ATP-binding cassette superfamily of transmembrane transporters and prevents the intracellular accumulation of many natural product-derived cytotoxic agents. See also: Elacridar (annotation moved to). Drug Indication Investigated for use/treatment in leukemia (myeloid) and myelodysplastic syndrome. Mechanism of Action P-glycoproteins are proteins which convert the energy derived from the hydrolysis of ATP to structural changes in protein molecules, in order to perform coupling, thus discharging medicine from cells. If P-glycoprotein coded with the MDR1 gene manifests itself in cancer cells, it discharges much of the antineoplastic drugs from the cells, making cancer cells medicine tolerant, and rendering antineoplastic drugs ineffective. This protein also manifests itself in normal organs not affected by the cancer (such as the liver, small intestine, and skin cells in blood vessels of the brain), and participates in the transportation of medicine. The compound Zosuquidar inhibits this P-glycoprotein, causing the cancer cells to lose their medicine tolerance, and making antineoplastic drugs effective. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (1.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 0.83 mg/mL (1.57 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 0.83 mg/mL (1.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8954 mL | 9.4769 mL | 18.9538 mL | |
| 5 mM | 0.3791 mL | 1.8954 mL | 3.7908 mL | |
| 10 mM | 0.1895 mL | 0.9477 mL | 1.8954 mL |