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| Targets |
Batabulin targets β-tubulin, binding to the colchicine-binding site with high affinity. This binding inhibits tubulin polymerization, preventing the formation of microtubules, which are essential for mitotic spindle formation and cell division. As a result, cells are arrested at the G2/M phase of the cell cycle and subsequently undergo apoptosis. Unlike paclitaxel, which stabilizes microtubules, batabulin destabilizes them, leading to mitotic catastrophe.
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| ln Vitro |
Following treatment with BatabuLin (T138067; 30-300 nM; 24 hours; MCF7 cells), cells exhibit a 25–30% tetraploid (4n) DNA content, suggesting that they are planning at the G2/M cell cycle boundary [1]. Treatment with T138067, 30–300 nM, and 24–48 hours on MCF7 cells revealed 25–30% of cells. After 48 hours, 50–80% of the cell population was observed with 100 nM BatabuLin [1]. By specifically and covalently binding to beta-tubulin isoforms, BatabuLin (T138067) prevents microtubule polymerization. At protected Cys-239 shared by the β1, β2, and β4 tubulin isoforms, covalent modification takes place. In BatabuLin, alterations in cell morphology, collapse, and a rise in cell ploidy were observed [1].
In vitro, batabulin demonstrates potent antiproliferative activity against a range of human cancer cell lines, including multidrug-resistant (MDR) variants. IC₅₀ values are typically in the low nanomolar range (1-20 nM) for various tumor types. It also inhibits endothelial cell proliferation and tube formation, suggesting antiangiogenic potential. The compound is more potent than colchicine in some assays and retains activity against P-glycoprotein-overexpressing cells, indicating it may circumvent certain drug resistance mechanisms. |
| ln Vivo |
The treatment of drug-sensitive CCRF-CEM tumors with batabuLin (T138067; 40 mg/kg; intraperitoneal injection; once weekly; days 5, 12, and 19; benzothoracic athymic nude mice) suppresses their growth [1].
In vivo, batabulin was evaluated in xenograft models of human cancers, including colon, lung, and breast cancer. It demonstrated significant tumor growth inhibition and tumor regression in some models at doses of 5-25 mg/kg administered intravenously. However, its in vivo activity was accompanied by a narrow therapeutic window, and in clinical trials, it showed only modest efficacy and dose-limiting toxicities, including myelosuppression and gastrointestinal effects, leading to its discontinuation. |
| Enzyme Assay |
In vitro tubulin polymerization assays for batabulin involve monitoring the polymerization of purified tubulin in the presence of GTP and varying concentrations of the compound. The polymerization is measured by turbidity at 350 nm over time. Batabulin inhibits polymerization in a concentration-dependent manner. Binding affinity to the colchicine site is determined using a competitive binding assay with [³H]-colchicine, where the IC₅₀ for displacement is calculated.
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| Cell Assay |
Cell Cycle Analysis[1]
Cell Types: MCF7 Cell Tested Concentrations: 30 nM, 100 nM and 300 nM Incubation Duration: 24 hrs (hours) Experimental Results: Shows arrest at G2/M cell cycle boundary. Apoptosis analysis[1] Cell Types: MCF7 Cell Tested Concentrations: 30 nM, 100 nM and 300 nM Incubation Duration: 24 hrs (hours) or 48 hrs (hours) Experimental Results: 25-30% of cells demonstrated diminished DNA content characteristic of apoptotic cells. In vitro cellular experiments for batabulin are performed using cancer cell lines (e.g., HCT-116, A549). Cells are treated with the compound (1-100 nM) for 24-72 hours. Cell viability is measured by MTT or CellTiter-Glo. Cell cycle analysis is done by propidium iodide staining and flow cytometry. Apoptosis is detected by Annexin V/PI or caspase-3 activation. The effects on microtubule network are visualized by immunofluorescence staining of β-tubulin. Resistance is assessed using MDR cell lines. |
| Animal Protocol |
Animal/Disease Models: Male athymic nude mice (nu/nu) (6-8 weeks old, 20-25 g) were injected with CCRF-CEM cells [1]
Doses: 40 mg/kg Route of Administration: intraperitoneal (ip) injection; once a week; Day 5, 12 and 19 Experimental Results: Growth of drug-sensitive CCRF-CEM tumors was impaired. In vivo animal studies for batabulin were conducted using mouse xenografts. The compound was administered intravenously (IV) or intraperitoneally (IP), typically once daily for 5 days or weekly. Tumor size was monitored, and tumor growth inhibition was calculated. Pharmacokinetic parameters and toxicity were assessed. The dose-limiting toxicities were identified as neutropenia and thrombocytopenia. Tumor tissue was analyzed for mitotic index and apoptosis. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of batabulin in humans and animals show a rapid clearance and a moderate half-life (2-4 hours in mice). It is metabolized by CYP450 enzymes, primarily CYP3A4, and is excreted in urine and feces. The compound has a high volume of distribution, indicating extensive tissue binding. Its oral bioavailability is poor, necessitating intravenous administration. The PK profile contributed to its narrow therapeutic index and eventual clinical failure.
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| Toxicity/Toxicokinetics |
The toxicity profile of batabulin is characterized by myelosuppression (neutropenia, thrombocytopenia) and gastrointestinal toxicity (nausea, vomiting, diarrhea) as dose-limiting toxicities. In preclinical studies, it caused mild hepatotoxicity and nephrotoxicity at high doses. Its neurotoxicity is lower than that of vinca alkaloids but is still a concern. The compound's development was stopped in Phase II due to an unfavorable risk-benefit ratio.
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| References | |
| Additional Infomation |
Batabulin is being investigated in the clinical trial NCT00057382 (T138067 vs. doxorubicin in patients with unresectable hepatocellular carcinoma who have not undergone chemotherapy). Batabulin is a synthetic pentafluorobenzenesulfonamide with potential antitumor activity. Batabulin covalently binds to β-tubulin, leading to microtubule polymerization disruption, cytoskeleton breakdown, cell cycle arrest, and tumor cell apoptosis.
Batabulin is a tubulin-binding agent targeting the colchicine site, developed as an anticancer drug. It showed potent in vitro activity but failed to demonstrate sufficient efficacy and acceptable toxicity in clinical trials. It is a representative of the class of vascular disrupting agents (VDAs) and antimitotic drugs. Although discontinued, it contributed to the understanding of tubulin-binding compounds and the importance of optimizing pharmacokinetic and toxicity profiles in drug development. |
| Molecular Formula |
C₁₃H₇F₆NO₃S
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|---|---|
| Molecular Weight |
371.26
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| Exact Mass |
371.005
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| CAS # |
195533-53-0
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| Related CAS # |
Batabulin sodium;195533-98-3
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| PubChem CID |
216324
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| Appearance |
White to off-white solid powder
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| Density |
1.629g/cm3
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| Boiling Point |
403.3ºC at 760mmHg
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| Flash Point |
197.7ºC
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| Vapour Pressure |
1.03E-06mmHg at 25°C
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| Index of Refraction |
1.535
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| LogP |
4.484
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
24
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| Complexity |
516
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=S(C1=C(F)C(F)=C(F)C(F)=C1F)(NC2=CC=C(OC)C(F)=C2)=O
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| InChi Key |
ROZCIVXTLACYNY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C13H7F6NO3S/c1-23-7-3-2-5(4-6(7)14)20-24(21,22)13-11(18)9(16)8(15)10(17)12(13)19/h2-4,20H,1H3
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| Chemical Name |
Benzenesulfonamide, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)-
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| Synonyms |
T 138067 T138067 T-138067 T-67T67 TL 057 Batabulin
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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 : ~100 mg/mL (~269.35 mM)
Ethanol : ~100 mg/mL (~269.35 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.73 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: ≥ 2.5 mg/mL (6.73 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 25.0 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: ≥ 2.5 mg/mL (6.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6935 mL | 13.4677 mL | 26.9353 mL | |
| 5 mM | 0.5387 mL | 2.6935 mL | 5.3871 mL | |
| 10 mM | 0.2694 mL | 1.3468 mL | 2.6935 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.
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