| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Dolastatin 15 (DLS-15), a natural peptide derived from Dolabella auricularia, is a potent mitotic inhibitor that is structurally similar to the Dolastatin 10. Dolastatin 15 can be used as the warhead in ADC by inducing cell cycle arrest and apoptosis in multiple myeloma cells, thus is called an apoptotic agent through Blc-2 phosphorylation.
Dolastatin 15 is a natural seven-subunit depsipeptide isolated from the marine mollusk Dolabella auricularia. It is structurally related to the well-known antimitotic agent Dolastatin 10 but exhibits less potent cytotoxic activity. As a potent antimitotic agent, it inhibits cell division by acting on tubulin and can be used as a cytotoxic payload (warhead) in antibody-drug conjugates (ADCs).| Targets |
The molecular target of Dolastatin 15 is tubulin. It binds weakly to the "vinca domain" on tubulin, a region physically close to but not identical with the specific binding site of Dolastatin 10 (the "peptide site"). This binding inhibits the polymerization of tubulin into microtubules, thereby disrupting mitotic spindle formation and leading to cell cycle arrest.
|
|---|---|
| ln Vitro |
Several human myeloma cell lines (RPMI8226, U266, and IM9) experience cell cycle arrest in the G2/M phase and subsequent apoptosis when exposed to dolastatin 15 (DLS 15). Through the activation of mitochondria and Fas (CD95)/Fas-L (CD95-L)-mediated pathways, dolastatin 15 causes apoptosis in myeloma cells [2]. All four SCLC cell lines (NCI-H69, NCI-H82, NCI-H345, and NCI-H446) are resistant to growth inhibition by dolastatin 15 (DLS 15), with IC50 values ranging from 0.039 to 28.8 nM, 2.7-9.2 times greater than the value of dolastatin. After being exposed to dolastatin 15, all four SCLC cell lines experienced G2/M arrest in less than a day [4].
|
| ln Vivo |
Dolastatin 15 binds to trastuzumab via the lysine residue at the drug's C terminus, targeting endogenously produced high HER2 levels of cells (i.e., SK-BR) that elicit target-dependent growth inhibition-3, SK-OV-3, in vitro, using a non-cleavable linker (trastuzumab-amide-C-term-Dol15). At varying doses (10 and 20 mg/kg), this ADC is efficacious against SK-OV-3 human ovarian cancer xenografts [3].
|
| Enzyme Assay |
The binding function is assessed using purified tubulin via a tubulin polymerization assay. Purified porcine brain tubulin is incubated with varying concentrations of Dolastatin 15 (e.g., 0 to 50 µM) in a glutamate-containing buffer at 37°C. Polymerization is followed by monitoring the increase in absorbance at 350 nm. Dolastatin 15 inhibits polymerization in a concentration-dependent manner with an IC₅₀ of approximately 23 µM for inhibition of tubulin polymerization, significantly higher than the 1.2 µM value for Dolastatin 10.
|
| Cell Assay |
Cytotoxicity is determined using standard cell proliferation assays. Tumor cells (e.g., L1210 cells) are seeded in 96-well plates and incubated overnight at 37°C in a 5% CO₂ incubator. The next day, fresh medium containing escalating concentrations of Dolastatin 15 (e.g., from 0.001 nM to 100 nM) is added, and the cells are incubated for an additional 48-72 hours. After incubation, viable cells are quantified using an MTT or CCK-8 assay, or DNA synthesis is assessed via [³H]-thymidine incorporation, and IC₅₀ values are calculated from concentration-inhibition curves. Alternatively, flow cytometry can be used to assess Dolastatin 15-induced cell cycle (G2/M phase) arrest.
|
| Animal Protocol |
An in vivo study described a protocol using a Dolastatin 15 ADC. Human ovarian cancer SK-OV-3 cells are implanted subcutaneously into female nude mice. When tumors reach approximately 100-200 mm³, the tumor-bearing mice are randomized into groups (n=6 per group). The Dolastatin 15 ADC (Trastuzumab-amide-C-term-Dol15) is administered via intravenous tail vein injection at doses of 10 and 20 mg/kg, once per week for several weeks. Tumor volumes and body weights are measured twice weekly with calipers to assess tumor growth inhibition and toxicity.
|
| ADME/Pharmacokinetics |
Detailed pharmacokinetic data for Dolastatin 15 itself is limited. However, information is available from a Phase I study of its water-soluble analog, LU103793. LU103793 was administered as a daily intravenous infusion for 5 days every 3 weeks. The volume of distribution at steady-state (Vss) was 7.6 ± 2.0 L/m², clearance was 0.49 ± 0.18 L/h/m², and the terminal elimination half-life (t₁/₂) was 12.3 ± 3.8 hours.
|
| Toxicity/Toxicokinetics |
The dose-limiting toxicities (DLTs) of the Dolastatin 15 analog LU103793 were determined in a Phase I clinical trial. DLTs included neutropenia, peripheral edema, and liver function test abnormalities at doses greater than 2.5 mg/m²/day. Four of six patients developed DLTs at the 3.0 mg/m²/day dose level, whereas two of 12 patients developed DLTs at the 2.5 mg/m²/day dose level. Prohibitive cardiovascular effects were not observed.
|
| References |
|
| Additional Infomation |
Dolastatin 15 has been reportedly discovered in the conch (Dolabella auricularia), and relevant data are available. Dolastatin 15 is a condensate initially isolated from the conch (Dolabella auricularia) and possesses potential antitumor activity. Compared to the structurally related compound doralastatin 10, doralastatin 15 exhibits lower activity; it binds weakly to tubulin, blocking microtubule assembly and thus inhibiting mitosis. Dolastatin 15 can also induce tumor cell apoptosis through a mechanism involving bcl-2, an oncoprotein overexpressed in certain cancers. (NCI04)
|
| Molecular Formula |
C45H68N6O9
|
|---|---|
| Molecular Weight |
837.07
|
| Exact Mass |
836.505
|
| CAS # |
123884-00-4
|
| PubChem CID |
9918978
|
| Appearance |
Typically exists as solid at room temperature
|
| Density |
1.2g/cm3
|
| Boiling Point |
943.2ºC at 760mmHg
|
| Flash Point |
524.2ºC
|
| Vapour Pressure |
0mmHg at 25°C
|
| Index of Refraction |
1.572
|
| LogP |
3.461
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
18
|
| Heavy Atom Count |
60
|
| Complexity |
1600
|
| Defined Atom Stereocenter Count |
7
|
| SMILES |
O=C(C1([H])C([H])([H])C([H])([H])C([H])([H])N1C(C([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N(C([H])([H])[H])C(C([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C(C([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N(C([H])([H])[H])C([H])([H])[H])=O)=O)=O)N1C([H])([H])C([H])([H])C([H])([H])C1([H])C(=O)OC([H])(C(N1C(C([H])=C(C1([H])C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])OC([H])([H])[H])=O)=O)C([H])(C([H])([H])[H])C([H])([H])[H]
|
| InChi Key |
LQKSHSFQQRCAFW-CCVNJFHASA-N
|
| InChi Code |
InChI=1S/C45H68N6O9/c1-26(2)36(46-40(53)37(27(3)4)47(9)10)42(55)48(11)38(28(5)6)43(56)49-22-16-20-31(49)41(54)50-23-17-21-32(50)45(58)60-39(29(7)8)44(57)51-33(34(59-12)25-35(51)52)24-30-18-14-13-15-19-30/h13-15,18-19,25-29,31-33,36-39H,16-17,20-24H2,1-12H3,(H,46,53)/t31-,32-,33-,36-,37-,38-,39-/m0/s1
|
| Chemical Name |
[(2S)-1-[(2S)-2-benzyl-3-methoxy-5-oxo-2H-pyrrol-1-yl]-3-methyl-1-oxobutan-2-yl] (2S)-1-[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxylate
|
| Synonyms |
DLS-15; NSC-617668; Dolastatin 15; 123884-00-4; J9ZKS885H5; NSC 617,668; NSC-617,668; DLS15; NSC 617668; Dolastatin 15
|
| 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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1946 mL | 5.9732 mL | 11.9464 mL | |
| 5 mM | 0.2389 mL | 1.1946 mL | 2.3893 mL | |
| 10 mM | 0.1195 mL | 0.5973 mL | 1.1946 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
