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Purity: ≥98%
Tigecycline (GAR936; GAR-936; TYGACL) is a potent tetracycline antibiotic which is bacteriostatic. It acts as a protein synthesis inhibitor by binding to the 30S ribosomal subunit of bacteria and thereby blocking entry of Aminoacyl-tRNA into the A site of the ribosome during prokaryotic translation.
| Targets |
Bacterial protein synthesis; FGFR1 (IC50 = 9.3 nM); FGFR2 (IC50 = 7.6 nM); FGFR3 (IC50 = 22 nM); FGFR4 (IC50 = 290 nM)
Bacterial 30S ribosomal subunit (antibacterial activity). [1] Mammalian mitochondrial ribosome (antileukemic activity; inhibition of mitochondrial protein translation). [1] |
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| ln Vitro |
AML2 cells and HL-60 cells are inhibited by tigecycline (0.63-30 μM, pre-eluted for 4 days, treated for 72 hours) with IC50 values of 4.72±0.54 and 3.06±0.85 μM, respectively (freshly produced). Tigecycline inhibits HL-60 cells and AML2 cells with IC50 values of 4.27±0.45 μM and 5.64±0.55 μM, one day prior to bias. With an IC50 of 5.02±0.60 and 4.39±0.44 μM (pre-biased for two days), tigecycline inhibits AML2. The IC50 values for cells and HL-60 cells, respectively, are 4.09±0.41 and 3.95±0.39 μM (pre-diluted for three days). After 4 days of pre-dilution in saline, tigecycline's capacity to suppress bleaching of TEX human cells decreased (from IC50~5 μM when freshly synthesized) to IC50>50 μM by CellTiter Flour Measure [1].
Tigecycline demonstrated antibacterial activity against E. coli (MG1655 strain) with a minimum inhibitory concentration (MIC) of 125 ng/mL when freshly prepared in saline. This antibacterial activity was lost after 4 days of preincubation in saline at room temperature (MIC >2 µg/mL), but was fully maintained (MIC = 125 ng/mL) when the drug was reconstituted in a novel formulation containing ascorbic acid (3 mg/mL) and pyruvate (60 mg/mL) in saline at pH 7.0 and protected from light. [1] Tigecycline exhibited antileukemic activity against human AML cell lines. The IC₅₀ against TEX cells was approximately 5 µM when freshly prepared in saline, as measured by the CellTiter Flour assay. After 4 days of preincubation in saline, this activity was lost (IC₅₀ >50 µM). However, when reconstituted in the novel ascorbic acid/pyruvate formulation, the antileukemic activity was preserved after the same 4-day preincubation, with IC₅₀ values maintained in TEX, OCI-AML2, and HL60 cells. [1] Tigecycline treatment of leukemic cells disrupted mitochondrial translation, leading to a decrease in the enzymatic activity of respiratory complex IV. This activity was lost after tigecycline was reconstituted in saline and incubated at room temperature for 5 days but was maintained when reconstituted in the ascorbic acid/pyruvate formulation. [1] |
| ln Vivo |
In NOD/SCID mice, tigecycline (50 mg/kg; intraperitoneally; twice daily; for 11 days) reduces tumor volume and weight [1]. In physiological saline, the peak plasma concentration (Cmax), terminal half-life (t1/2), area under the plasma concentration-time curve (AUC), clearance rate (CL), and distribution concentration (Vz) of tigecycline are, respectively, 22.8μg/mL, 108.9 min, 1912.2minμg/mL, 26.1 mL/min/kg, 4109.4 mL/kg. In tigecycline formulation (60 mg/mL pyruvate, 3 mg/mL ascorbic acid, physiological saline), the peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), clearance (CL), and distribution waveform (Vz) are 15.7 μg/mL, 110.3 min, 2036.5 minμg/mL, 24.6 mL/min/kg, and 3906.2 mL/kg.
In an AML xenograft model using NOD/SCID mice engrafted subcutaneously with OCI-AML2 cells, treatment with tigecycline (50 mg/kg, intraperitoneal injection, twice daily for 11 days) significantly reduced tumor volume and weight compared to vehicle controls. The novel ascorbic acid/pyruvate formulation of tigecycline showed similar efficacy. [1] Tumors excised from mice treated with tigecycline or its novel formulation showed reduced expression of mitochondrially-translated proteins Cox-1 and Cox-2, indicating sustained inhibition of mitochondrial translation in vivo. The expression of nuclear-encoded Cox-4 was unchanged. [1] |
| Enzyme Assay |
Respiratory Complex IV Activity Assay: The enzymatic activity of respiratory complex IV (cytochrome c oxidase) was measured in TEX human leukemia cells treated with tigecycline. This activity decreases upon inhibition of mitochondrial translation. The assay confirmed that the activity was lost when tigecycline was reconstituted in saline and preincubated for 5 days but was maintained when reconstituted in the ascorbic acid/pyruvate formulation. [1]
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: Human leukemia OCI-AML2, HL-60 (ATCC) and TEX cell lines Tested Concentrations: 0.63-30 µM Incubation Duration: 4 days of pre-incubation, 72 hrs (hours) of treatment Experimental Results: Inhibition of AML2 cells and HL- 60 cells, IC50 are 4.72±0.54 and 3.06±0.85 μM respectively (freshly prepared). Cell Viability Assay (CellTiter Flour): Human leukemia cells (TEX, OCI-AML2, HL60) were seeded in culture plates and treated with tigecycline (freshly prepared or preincubated) for 72 hours. Cell viability was then measured using the CellTiter Flour assay to determine the half-maximal inhibitory concentration (IC₅₀). [1] Immunoblotting: Total proteins were extracted from cultured cells or excised mouse tumors. Proteins were separated by electrophoresis, transferred to a PVDF membrane, and probed with antibodies against mitochondrial proteins Cox-1, Cox-2, and nuclear-encoded Cox-4. The membrane was stained with 0.1% Amido Black for total protein loading control. [1] |
| Animal Protocol |
Animal/Disease Models: NOD/SCID Mouse OCI-AML2 acute myeloid leukemia (AML) xenograft model [1]
Doses: 50 mg/kg Route of Administration: intraperitoneal (ip) injection; for 7) [1]. twice (two times) daily; continued for 11 days Experimental Results: Reduction in tumor volume and weight. Animal/Disease Models: NOD/SCID (severe combined immunodeficient) mouse[1] Doses: 50 mg/kg Route of Administration: intraperitoneal (ip) injection; 360 minutes Experimental Results: peak plasma concentration (Cmax), terminal half-life (t1/2), plasma concentration-time The area under the curve (AUC), clearance (CL) and distribution volume (Vz) were all 22.8 μg/108.9 minutes, 1912.2 minutesμg/ml, 26.1 ml/minute/kg, and 4109.4 ml/kg respectively. Pharmacokinetic Study in Mice: Mice were administered a single intraperitoneal injection of tigecycline (50 mg/kg) or the novel tigecycline formulation (50 mg/kg). Blood plasma was collected at increasing time points post-injection. Plasma tigecycline concentration was determined using HPLC. Pharmacokinetic parameters (Cmax, t½, AUC, CL, Vz) were calculated using WinNonlin software. [1] AML Xenograft Efficacy Study: NOD/SCID mice were subcutaneously injected with OCI-AML2 human leukemia cells. When tumors became palpable (approximately 11 days post-injection), mice were treated with intraperitoneal injections of saline (vehicle control), formulation solvent, tigecycline in saline (50 mg/kg), or the novel tigecycline formulation (50 mg/kg), twice daily for 11 days. Tumor volume was monitored, and mice were sacrificed on day 11 for tumor excision and weighing. [1] Tolerability Study: NOD/SCID mice were administered daily intraperitoneal injections of the novel formulation (ascorbic acid and pyruvate in saline, pH 7.0) or an equivalent volume of saline, 5 days per week for 3 weeks. Body weight and behavior were monitored. At the end of the study, blood was collected for serum chemistry analysis (bilirubin, AST, ALP, creatine kinase), and organs (heart, liver, kidney, muscle) were harvested for histological examination (H&E staining). [1] |
| ADME/Pharmacokinetics |
Following intraperitoneal injection in mice, tigecycline and its novel formulation (containing ascorbic acid and pyruvate) exhibited similar pharmacokinetic characteristics. The terminal half-life (t½) of the novel formulation was approximately 110.3 minutes, while that of tigecycline was approximately 108.9 minutes. Other parameters (Cmax, AUC, CL, Vz) were also comparable between the two. [1]
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| Toxicity/Toxicokinetics |
The novel tigecycline formulation (ascorbic acid and pyruvate dissolved in saline) was well tolerated in mice. No changes in behavior or weight were observed in mice after 3 weeks of intraperitoneal administration (5 days a week). Serum markers of liver function (total bilirubin, AST, ALP) and muscle damage (creatine kinase) were not significantly different from those in the saline control group. Histological examination of the heart, liver, kidneys and muscle tissues revealed no abnormalities visible to the naked eye or under a microscope. [1]
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| References |
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| Additional Infomation |
Tigecycline is a tetracycline derivative in which the hydroxyl group at position 5 and the methyl group at position 6 are replaced by hydrogen atoms, and the 7 and 9 positions are replaced by dimethylamino and (N-tert-butylglycyl)amino groups, respectively. It is a glycylcycline antibiotic with antibacterial activity against a variety of Gram-positive and Gram-negative bacteria, including tetracycline-resistant bacteria. It is used intravenously to treat complicated skin and soft tissue infections caused by susceptible bacteria. It is an antibacterial drug. It belongs to the tetracycline class of compounds and is a tert-α-hydroxy ketone. It is the conjugate base of tigecycline (1+). Tigecycline is a tetracycline antibacterial drug. It is a tetracycline derivative that can act as a protein synthesis inhibitor. It is used as a systemic antibacterial drug to treat complicated skin and intra-abdominal infections. It is also used to treat community-acquired pneumonia. See also: Tigecycline (note moved to).
Tigecycline is a broad-spectrum glycylcycline antibiotic approved for the treatment of complicated cutaneous/intra-abdominal infections and community-acquired pneumonia. It also has antileukemic activity by inhibiting the translation of mitochondrial proteins in acute myeloid leukemia (AML) cells. [1] A novel stabilizer has been developed to improve the stability of reconstituted tigecycline. The formulation contains ascorbic acid (3 mg/mL) and pyruvate (60 mg/mL), dissolved in physiological saline at pH 7.0, and should be stored protected from light. Compared to rapid degradation when dissolved alone in physiological saline, the formulation retains more than 90% of its integrity when stored at room temperature protected from light for at least 7 days. The degradation of tigecycline follows first-order kinetics and is accelerated by light exposure. [1] This novel formulation retains the antibacterial and antileukemic activity of tigecycline after prolonged pre-incubation, maintains its pharmacokinetic characteristics in vivo, and is well tolerated in mice. [1] |
| Molecular Formula |
C29H39N5O8
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|---|---|
| Molecular Weight |
585.65
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| Exact Mass |
585.279
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| Elemental Analysis |
C, 59.47; H, 6.71; N, 11.96; O, 21.86
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| CAS # |
220620-09-7
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| Related CAS # |
Tigecycline tetramesylate;Tigecycline hydrochloride;197654-04-9;Tigecycline mesylate;1135871-27-0;Tigecycline hydrate;1229002-07-6;Tigecycline-d9;2699607-86-6
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| PubChem CID |
54686904
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
890.9±65.0 °C at 760 mmHg
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| Melting Point |
164-166°C
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| Flash Point |
492.6±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.675
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| LogP |
-1.3
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| Hydrogen Bond Donor Count |
7
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
42
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| Complexity |
1240
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| Defined Atom Stereocenter Count |
4
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| SMILES |
CC(C)(C)NCC(=O)NC1=CC(=C2C[C@H]3C[C@H]4[C@@H](C(=O)C(=C([C@]4(C(=O)C3=C(C2=C1O)O)O)O)C(=O)N)N(C)C)N(C)C
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| InChi Key |
SOVUOXKZCCAWOJ-HJYUBDRYSA-N
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| InChi Code |
InChI=1S/C29H39N5O8/c1-28(2,3)31-11-17(35)32-15-10-16(33(4)5)13-8-12-9-14-21(34(6)7)24(38)20(27(30)41)26(40)29(14,42)25(39)18(12)23(37)19(13)22(15)36/h10,12,14,21,31,36-37,40,42H,8-9,11H2,1-7H3,(H2,30,41)(H,32,35)/t12-,14-,21-,29-/m0/s1
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| Chemical Name |
(4S,4aS,5aR,12aR)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide
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| Synonyms |
GAR-936; GAR936; Tigecycline; 220620-09-7; Tygacil; WAY-GAR-936; GAR-936; TYGACL; Tigecycline
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~42.69 mM)
H2O : ~8.33 mg/mL (~14.22 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.27 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.08 mg/mL (3.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 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. View More
Solubility in Formulation 3: 36.67 mg/mL (62.61 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7075 mL | 8.5375 mL | 17.0750 mL | |
| 5 mM | 0.3415 mL | 1.7075 mL | 3.4150 mL | |
| 10 mM | 0.1708 mL | 0.8538 mL | 1.7075 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Antibiotic Therapy for Infectious Diseases
CTID: NCT04937894
Phase: Status: Recruiting
Date: 2021-06-24
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Products are for research use only; We do not sell to patients
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