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Ansamitocin P-3 (Maytansinol isobutyrate; NSC-292222; Antibiotic C 15003P3) is a potent microtubule/antimitotic inhibitor used as an warhead of ADC (antibody drug conjugate). With high antiproliferative activity, ansamitocin P-3 is a macrocyclic antibiotic that fights cancer.
| Targets |
Maytansinoids
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|---|---|
| ln Vitro |
Ansamitocin p-3, at a high concentration of 80 μM, does not cause tubulin to aggregation, in contrast to VCR, which totally inhibits the polymerization of tubulin isolated from bovine brains at 5 μM. Additionally, the polymerized tubulin is potently depolymerized by ansamitocin p-3 at 16 μM (IC50 = 3.8 μM). When culture cells are exposed to a specific concentration of dibutyryl cyclic adenosine 3':5'-monophosphate, the morphological change of AC cells from fibroepithelioid to glial cell type is prevented by the addition of ansamitocin p-3. Furthermore, the well-defined network of cytoplasmic microtubules in A31 cells rapidly disperses upon treatment with 16 nM ansamitocin p-3. Ansamitocin p-3 treatment for a brief period of time also prevents A31 or KB cells from synthesizing DNA. These findings demonstrate that ansamitocin p-3 inhibits mitotic spindle fiber formation and, ultimately, cytokilling by interfering with the microtubule assembly system. [1] Ansamitocin p-3 exhibits strong cytotoxicity in a dose-dependent manner against A-549, HT-29, and MCF-7 cells, with corresponding ED50 values of 4 ×10-7, 4 × 10-7, and 2 × 10-6 μg/mL. [2] Ansamitocin p-3 likewise demonstrates cytotoxicity with a significantly lower EC50 of 0.081 nM against HCT-116 cells. [3] In a p53-dependent manner, ansamitocin p-3 amplifies the effects of radiation in both human cancer cells and Drosophila cells.[4]
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| ln Vivo |
Ansamitocin P-3 treatment (>1 μg) causes an increased arrest in the metaphase of P388 leukemia cells and significantly suppresses the growth of leukemia SN36. Treatment with ansamitocin p-3 at a dose of 25 μg/kg/day considerably increases the survival period of mice with i.p. B16 melanoma by 130%. The treatment of mice with Ehrlich ascites carcinoma, Sarcoma 180, and P815 mastocytoma with ansamitocin p-3 also significantly extends their survival time; however, the treatment only marginally extends the survival time of mice with ascites MOPC-104E myeloma, leukemia L1210, and leukemia C1498.[1]
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| Enzyme Assay |
After adding 400 μL of bovine tubulin solution (1 mg/mL in cold MES buffer) and keeping it at 0 °C for 10 to 15 minutes, the mixture is warmed in a water bath at 37 °C for 30 to 60 minutes. Ansamitocin p-3 solution (GTP minus MES buffer) or 1 M Tris buffer, pH 8.4 (for blank) are added in various concentrations. As a result of the tubulin polymerization, the mixture becomes more turbid when it gets heated. It uses a Hitachi type 101 spectrophotometer to measure turbidity at 460 nm.
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| Cell Assay |
Following cell synchronization, different Ansamitocin p-3 concentrations are applied for approximately 24 hours. A volume of 1 mL is used to label cells with [3H]thymidine (5 Ci/mM, 1 μCi/mL). The cells on coverslips are fixed with a 3:1 ratio of methanol to acetic acid following an hour of pulse labeling at 37 °C. Each coverslip's radioactivity is measured using a liquid scintillation counter after the acidsoluble fraction has been removed from the cells.
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| Animal Protocol |
Female DBA/2 mice bearing P388, L1210, or P815 cells, C57BL/6 mice bearing B16, or C1498 cells, ICR mice bearing sarcoma 180 and EAC, and BALB/c mice bearing MOPC-104E cells
~200 μg/kg Administered i.p. or i.v. daily |
| References | |
| Additional Infomation |
Ansamitocin P3 is a polyketide antibiotic that is isolated from Actinosynnema pretiosum and also exhibits antitumour activity. It has a role as an antimicrobial agent, a metabolite and an antineoplastic agent. It is a polyketide, a macrocycle, a lactam, an epoxide, a carboxylic ester, a carbamate ester, an aromatic ether and a member of monochlorobenzenes.
Ansamitocin P-3 has been reported in Thamnobryum sandei, Isothecium subdiversiforme, and other organisms with data available. Ansamitomicin P-3 is an ansamacrolide and maytansine analogue originally isolated from the Ethiopian shrub Maytenus serrata with antineoplastic activity. Ansamitomicin P-3 binds to tubulin at the maytansine-binding site, thereby inhibiting microtubule assembly, inducing microtubule disassembly, and disrupting mitosis. |
| Molecular Formula |
C32H43CLN2O9
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|---|---|
| Molecular Weight |
635.14482
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| Exact Mass |
634.265
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| Elemental Analysis |
C, 60.51; H, 6.82; Cl, 5.58; N, 4.41; O, 22.67
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| CAS # |
66584-72-3
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| Related CAS # |
66547-09-9 (AP-3');66584-72-3 (AP-3);
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| PubChem CID |
5282049
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| Appearance |
White to off-white solidw powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
833.1±65.0 °C at 760 mmHg
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| Melting Point |
190-192℃
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| Flash Point |
457.7±34.3 °C
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| Vapour Pressure |
0.0±3.2 mmHg at 25°C
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| Index of Refraction |
1.583
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| LogP |
5.09
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
44
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| Complexity |
1150
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| Defined Atom Stereocenter Count |
7
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| SMILES |
ClC1=C(N(C)C(C[C@H](OC(C(C)C)=O)[C@@](O2)(C)[C@]2([H])[C@H](C)[C@]3([H])C[C@](NC(O3)=O)(O)[C@H](OC)/C=C/C=C(C)/C4)=O)C=C4C=C1OC
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| InChi Key |
OPQNCARIZFLNLF-JBHFWYGFSA-N
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| InChi Code |
InChI=1S/C32H43ClN2O9/c1-17(2)29(37)43-25-15-26(36)35(6)21-13-20(14-22(40-7)27(21)33)12-18(3)10-9-11-24(41-8)32(39)16-23(42-30(38)34-32)19(4)28-31(25,5)44-28/h9-11,13-14,17,19,23-25,28,39H,12,15-16H2,1-8H3,(H,34,38)/b11-9+,18-10+/t19-,23+,24-,25+,28+,31+,32+/m1/s1
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| Chemical Name |
[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate
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| Synonyms |
NSC292222; NSC-292222; NSC 292222; Maytansinol isobutyrate; Ansamitocin P-3; Maytansinoid AP-3
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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 (~157.5 mM)
Ethanol: ~55 mg/mL (~86.6 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.94 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 (3.94 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 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 (3.94 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 | 1.5745 mL | 7.8723 mL | 15.7446 mL | |
| 5 mM | 0.3149 mL | 1.5745 mL | 3.1489 mL | |
| 10 mM | 0.1574 mL | 0.7872 mL | 1.5745 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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