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| Targets |
VAL-083 targets DNA, specifically creating N7 methylation on guanine residues. This alkylation leads to DNA damage, including cross-linking and strand breaks, which ultimately results in cell cycle arrest and apoptosis. VAL-083 is a bi-functional alkylating agent, meaning it can form cross-links between DNA strands, which are particularly difficult for cells to repair. The compound's ability to cross the blood-brain barrier makes it relevant for the treatment of brain tumors. Its selectivity for tumor cells suggests that it may preferentially target cancer cells over normal cells.
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| ln Vitro |
N7 methylation of DNA is produced by the alkylating chemical VAL-083. After 72 hours, VAL-083 stimulates cell proliferation while inhibiting that of U251 and SF188. SF188 growth is inhibited by VAL-083 (5 μM) by almost 95%. T98G cell proliferation is dose-dependently inhibited by VAL-083 (IC50 <5 μM)[1]. At concentrations more than 12.5 μg/mL, VAL-083 (dihydrogalactitol) inhibits the growth of HUVEC and U251 cells. In HUVEC and U251 cells, VAL -083 (3.125, 6.25, 12.5 μg/mL) also decreases MMP2, VEGF, VEGFR2, and FGF2 production in addition to inhibiting migration and threshold [2]. In three neuroastrocytoma cells, VAL-083 (1,2:5,6-dianhydrogalactitol, 1,2,5 μM) dose-dependently initiates the cell cycle in the G2/M phase. The two parallel signaling cascades that VAL-083 activates are the CDC25C-CDK1 and p53-p21 cascades. Furthermore, VAL-083 markedly improved LN229's ability to target cellular radiation [3].
In vitro, VAL-083 inhibits the growth of T98G cells with an IC50 <5 μM. At doses >12.5 μg/mL, it inhibits the proliferation of HUVEC and U251 cells. VAL-083 inhibits U251 and SF188 cell growth and induces apoptosis after 72 hours. VAL-083 (5 μM) inhibits the growth of SF188 cells by approximately 95%. Its potent antiproliferative activity has been demonstrated across multiple cancer cell lines. |
| ln Vivo |
In zebrafish models, VAL-083 (DianHydrgalactitol; 25, 50, and 100 μg/mL) quantitatively suppresses angiogenesis. At 25 μg/mL, VAL-083 dramatically lowers the expression of VEGF, VEGFR2, and FGF2, and at 50 μg/mL, it further reduces the expression of FGFR2 [2]. The growth of mice LN229 cells is markedly inhibited by VAL-083 (1,2:5,6-divided galactitol; 5 mg/kg, intravenously, twice a week for 6 weeks), as compared to tumor growth rate (T/C) of 22.38% and tumor growth inhibition rate (TGI) of 83.58%. Furthermore, in xenograft tumor models, VAL-083 markedly activates the CDC25C-CDK1 cascade [3].
In vivo, VAL-083 has been investigated for its potential antineoplastic activity. Its ability to cross the blood-brain barrier makes it a promising candidate for the treatment of brain tumors. VAL-083 appears to be selective for tumor cells. However, detailed in vivo efficacy data from animal models are limited. Clinical studies have been conducted to evaluate its safety and efficacy. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cell) assays for VAL-083 involve studying its DNA alkylating activity. DNA is incubated with VAL-083, and the formation of N7-methylguanine adducts is measured using mass spectrometry or other analytical methods. DNA cross-linking is assessed using gel electrophoresis or other techniques.
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| Cell Assay |
In vitro cell-based experiments for VAL-083 are conducted using cancer cell lines, including glioblastoma and other tumor types. Cells are treated with VAL-083 at varying concentrations, and cell viability, proliferation, and apoptosis are assessed using standard assays (e.g., MTT, CellTiter-Glo). DNA damage is assessed by measuring γH2AX foci formation or comet assays.
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| Animal Protocol |
In vivo animal experiments for VAL-083 are performed in xenograft mouse models of cancer, particularly brain tumors. VAL-083 is administered, and tumor growth, survival, and DNA damage markers are assessed. Clinical trials in humans have also been conducted.
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| ADME/Pharmacokinetics |
VAL-083 is a small molecule (MW 146.14, formula C6H10O4) with suitable physicochemical properties for crossing the blood-brain barrier. The compound has a molecular weight of 146.14 g/mol. Detailed pharmacokinetic parameters are available from clinical studies.
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| Toxicity/Toxicokinetics |
Preclinical and clinical toxicology studies have been conducted to evaluate the safety profile of VAL-083. As an alkylating agent, VAL-083 has the potential for myelosuppression, gastrointestinal toxicity, and other side effects associated with DNA-damaging agents. Clinical trials have evaluated the safety and efficacy of VAL-083 in cancer patients.
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| References |
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| Additional Infomation |
Dihydrogalactitol has been used in clinical trials for the treatment of glioblastoma, glioma, glioblastoma, brain cancer, and glioblastoma multiforme. Dihydrogalactitol is a bifunctional hexetol derivative with potential antitumor activity. It can disrupt DNA function and cause cell cycle arrest through alkylation and cross-linking of DNA via epoxy groups at all stages of the cell cycle. (NCI04) Dihydrogalactitol is a cytotoxic dihalohexetol that can disrupt DNA function and cause cell cycle arrest through alkylation and cross-linking of DNA via epoxy groups at all stages of the cell cycle. It has antitumor activity but can also cause myelotoxicity.
VAL-083 is also known as Dianhydrodulcitol and is a bi-functional alkylating agent. It is a hexitol derivative that creates N7 methylation on DNA. The compound has been investigated for the treatment of various cancers, including glioblastoma and other brain tumors. Its ability to cross the blood-brain barrier and its selectivity for tumor cells make it a unique agent in cancer research. The compound is not approved for clinical use. |
| Molecular Formula |
C6H10O4
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| Molecular Weight |
146.14
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| Exact Mass |
146.058
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| CAS # |
23261-20-3
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| PubChem CID |
15942827
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| Appearance |
White to off-white solid powder
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| Density |
1.567
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| Boiling Point |
348ºC at 760mmHg
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| Flash Point |
164.3ºC
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| LogP |
-1.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
10
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| Complexity |
122
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C1[C@@H](O1)[C@@H]([C@@H]([C@@H]2CO2)O)O
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| InChi Key |
AAFJXZWCNVJTMK-GUCUJZIJSA-N
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| InChi Code |
InChI=1S/C6H10O4/c7-5(3-1-9-3)6(8)4-2-10-4/h3-8H,1-2H2/t3-,4+,5+,6-
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| Chemical Name |
(1S,2R)-1-[(2S)-oxiran-2-yl]-2-[(2R)-oxiran-2-yl]ethane-1,2-diol
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| Synonyms |
VAL083; VAL083; VAL083
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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 : ~200 mg/mL (~1368.55 mM)
DMF :≥ 100 mg/mL (~684.28 mM) H2O : ~50 mg/mL (~342.14 mM) |
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| 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 | 6.8428 mL | 34.2138 mL | 68.4275 mL | |
| 5 mM | 1.3686 mL | 6.8428 mL | 13.6855 mL | |
| 10 mM | 0.6843 mL | 3.4214 mL | 6.8428 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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