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UNBS5162 is a novel naphthalimide that binds to DNA by intercalation and suppresses CXCL chemokine elaboration. In orthotopic human prostate cancer models, in vivo UNBS5162 administration resulted in a significant increase in survival. The National Cancer Institute (NCI) obtained results using UNBS3157 and UNBS5162 against the NCI 60 cell line panel. These results did not demonstrate a correlation with any other compound in the NCI database, including amonafide. This suggests that these two novel naphthalimides have a unique mechanism of action.
| Targets |
CXCL
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|---|---|
| ln Vitro |
After five days of exposure to 1 µM of UNBS5162, PC-3 cells exhibit a significant reduction in the expression of proangiogenic CXCL chemokines. With IC50 values of 17.3 μM, 16 μM, 4.7 μM, 8.5 μM, 28.8 μM, 8.9 μM, 46.5 μM, 21.2 μM, and 9.1 μM in PC-3, DU-145, U373-MG, Hs683, HCT-15, LoVo, MCF-7, A549, and Bx-PC-3 cells, UNBS5162 exhibits feeble in vitro antiproliferative activity. UNBS5162 significantly reduces the growth kinetics of PC-3 tumor cells at 10 µM without causing senescence, while DU-145 cells exhibit the opposite effect. This discrepancy could be caused by their different p53 statuses or by how much p16 is expressed. UNBS5162 exhibits no antitumor effects at 1 µM. In PC-3 cells, UNBS5162 at 10 µM significantly raised the amounts of heterochromatin by increasing the number of histones, at least at the mRNA levels[1].
UNBS5162 has been shown to effectively inhibit the growth of tumor cells both in vitro and in vivo, as well as to lower levels of CXC chemokine ligand (CXCL) chemokines, such as CXCL1, CXCL5, and CXCL8, in experimental prostate cancer. In SKOV3 ovarian cancer cells, it suppresses cell invasion, migration, and proliferation while promoting cell apoptosis, possibly via the PI3K/AKT signaling pathway[2]. |
| ln Vivo |
UNBS5162, In vivo administration increases survival in orthotopic human prostate cancer models significantly after repeated administration. Systemic exposure following oral administration of 80 mg/kg is relatively low in female mice used to test the pharmacokinetic profiles of UNBS5162 (Cmax = 510 ng/ml and AUC0-∞ = 886 ng·h/ml), as indicated by an absolute bioavailability of only 3.84%. It is estimated that the volume of distribution (Vd) is 18.9 L/kg and the total clearance is 3.47 L/h per kilogram. Following intravenous administration of 20 mg/kg UNBS5162, the half-life is predicted to be 3.8 hours. While 1-µM levels can last up to two hours, post-i.v. UNBS5162 plasma levels of 10 µM are only sustained for about thirty minutes[1].
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| Animal Protocol |
Mice: Male 6-week-old nu/nu mice (n = 9 per treatment group) have their prostates injected with 2.5 × 106 human PC-3 or DU-145 cells to create orthotopic xenografts. Saline/Rompun/Imalgene anesthesia (5:1:1 by volume) is used for all graft procedures. After the tumor-bearing mice receive UNBS3157, UNBS5162, or reference anticancer agents (taxol, mitoxantrone, and amonafide), their survival period serves as the end point of these orthotopic experiments. For moral reasons, however, animals are put to death if they lose 20% of their body weight from what was measured before the tumor was grafted. Three times a week, the weight of every animal is taken. To verify tumor development, autopsies and histologic diagnoses are carried out on every mouse; a 100% success rate is attained. The tumors from mice treated with the drug (10 mg/kg, intravenous (i.v.)) and those treated with the vehicle are removed from the animals in the UNBS5162 experiments conducted in the PC-3 model, fixed in buffered formalin, embedded in paraffin, and 5-µm-thick sections are taken. Hematoxylin and eosin staining is subsequently applied to these histologic slides in order to count the blood vessels[1].
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| References |
| Molecular Formula |
C17H18N4O3
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|---|---|
| Molecular Weight |
326.349823474884
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| Exact Mass |
326.14
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| Elemental Analysis |
C, 62.57; H, 5.56; N, 17.17; O, 14.71
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| CAS # |
956590-23-1
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| Related CAS # |
956590-23-1
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| Appearance |
Yellow solid powder
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| SMILES |
CN(C)CCN1C(=O)C2=CC=CC3=CC(=CC(=C32)C1=O)NC(=O)N
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| InChi Key |
WCKZRLOUKYFJDY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H18N4O3/c1-20(2)6-7-21-15(22)12-5-3-4-10-8-11(19-17(18)24)9-13(14(10)12)16(21)23/h3-5,8-9H,6-7H2,1-2H3,(H3,18,19,24)
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| Chemical Name |
[2-[2-(dimethylamino)ethyl]-1,3-dioxobenzo[de]isoquinolin-5-yl]urea
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| Synonyms |
UNBS 5162; UNBS-5162; UNBS5162
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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: 17~21.5 mg/mL (52.1~65.9 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 | 3.0642 mL | 15.3210 mL | 30.6419 mL | |
| 5 mM | 0.6128 mL | 3.0642 mL | 6.1284 mL | |
| 10 mM | 0.3064 mL | 1.5321 mL | 3.0642 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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