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| Targets |
Heptamidine dimethanesulfonate targets the calcium-binding protein S100B. S100B is a member of the S100 family of calcium-binding proteins that is highly expressed in melanoma cells. It plays a critical role in cell proliferation, migration, and invasion. S100B is also involved in the regulation of p53, a tumor suppressor protein. By binding to S100B, Heptamidine dimethanesulfonate inhibits its function, leading to selective killing of melanoma cells that express S100B. The compound also inhibits Trypanosoma brucei, suggesting that it may have multiple targets or that its activity against parasites is mediated through a different mechanism. The compound's ability to selectively kill S100B-expressing melanoma cells makes it a promising candidate for melanoma therapy.
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| ln Vitro |
Heptamidine is an S100B-pentamidine complex. In every S100B monomer, two pentamidine molecules are combined. It is an S100B inhibitor [1]. HeLa cells expressing 960 CUG repeats show cytotoxicity at concentrations greater than 17.5 μM for heptamidine (20 μM), which does not significantly lower CUG levels in comparison to propamidine and pentamidine [2]. With an EC50 value of 15 μM, heptemidine can correct the mis-splicing of tiny gene reporter genes in the HeLa cell DM1 model [2].
In vitro, Heptamidine dimethanesulfonate binds to S100B with a Kd of 6.9 μM. It selectively kills melanoma cells that express S100B over those that do not. This selectivity is a key feature of the compound, as it suggests that it can specifically target melanoma cells while sparing normal cells that do not express S100B. The compound's activity against melanoma cells is dose-dependent, and its effects on cell viability can be measured using cell viability assays. The compound also inhibits Trypanosoma brucei, indicating that it has antiparasitic activity. However, the mechanism of its antiparasitic activity is not fully understood. |
| ln Vivo |
In HSALR mice, heptamidine (ip; 20 or 30 mg/kg; 7 days) reduced exon 7a inclusions in a dose-dependent manner, with wild-type levels being reached at the 20 mg/kg dose (6±1%). Similarly, at doses of 20 or 30 mg/kg, myotonia decreased from grade 3 to grade 1 (sporadic myotonic discharges) or grade 0 [2].
Detailed in vivo activity data for Heptamidine dimethanesulfonate is not extensively reported in the available literature. However, its in vitro ability to selectively kill S100B-expressing melanoma cells suggests that it may have potential for treating melanoma in vivo. Typically, the in vivo efficacy of anticancer compounds is evaluated in xenograft mouse models. In such a study, immunodeficient mice are implanted with melanoma cells that express S100B. When tumors reach a certain size, Heptamidine dimethanesulfonate is administered orally or intraperitoneally at various doses. Tumor volume is measured regularly, and final tumor weights are recorded. The compound's ability to inhibit tumor growth is assessed by comparing tumor volumes and weights between treated and control groups. The compound's in vivo activity would depend on its pharmacokinetic properties, such as oral bioavailability and tissue distribution. The compound's ability to inhibit Trypanosoma brucei suggests that it may also have potential for treating African trypanosomiasis in vivo. However, further studies are needed to evaluate the compound's in vivo efficacy and safety. |
| Enzyme Assay |
The binding of Heptamidine dimethanesulfonate to S100B is typically measured using a surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) assay. In an SPR assay, S100B is immobilized on a sensor chip. Varying concentrations of Heptamidine dimethanesulfonate are flowed over the chip, and the binding is measured as a change in refractive index. The association and dissociation rates are determined, and the Kd is calculated from the ratio of the dissociation rate to the association rate. In an ITC assay, S100B is titrated with Heptamidine dimethanesulfonate, and the heat released or absorbed upon binding is measured. The binding isotherm is fitted to a model to determine the Kd and the stoichiometry of binding. These assays provide a direct measure of the compound's affinity for S100B. The compound's selectivity for S100B over other calcium-binding proteins can be assessed using similar assays.
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| Cell Assay |
For in vitro cellular assays, the effect of Heptamidine dimethanesulfonate on melanoma cell viability is typically assessed using melanoma cell lines that express S100B, such as A375 or SK-MEL-28 cells. Cells are seeded in 96-well plates at a density of approximately 5 × 10³ cells per well and allowed to attach overnight. The cells are then treated with Heptamidine dimethanesulfonate at various concentrations (e.g., 1-100 μM) for 48-72 hours. Cell viability is assessed using an MTT or resazurin assay. In the MTT assay, viable cells with active mitochondria reduce MTT to a purple formazan product, which is solubilized and measured spectrophotometrically. The absorbance is directly proportional to the number of viable cells. The percentage of cell viability at each compound concentration is calculated relative to untreated control cells. The IC₅₀, representing the concentration that reduces cell viability by 50%, is determined from the dose-response curve. The selectivity of the compound for S100B-expressing cells is assessed by comparing its effects on S100B-expressing melanoma cells to its effects on cells that do not express S100B.
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| Animal Protocol |
Animal/Disease Models: Line 20b homozygous HSALR transgenic mice (FVB inbred background) with myotonic dystrophy (DM) mouse model [2]
Doses: 20 or 30 mg/kg Route of Administration: intraperitoneal (ip) injection; Injection. 7 days; one time/day Experimental Results: Reversal of splicing defects and rescue of myotonia in mouse model of DM. For in vivo efficacy studies, a xenograft mouse model is commonly employed. Six- to eight-week-old female athymic nude mice are injected subcutaneously in the flank with 5 × 10⁶ S100B-expressing melanoma cells (e.g., A375 cells) suspended in Matrigel. When tumors reach a volume of approximately 100-150 mm³, the mice are randomized into treatment groups (n=6-8 per group). Heptamidine dimethanesulfonate is formulated in a suitable vehicle, such as a solution in DMSO/PEG300/Tween-80/saline. The compound is administered orally or intraperitoneally at various doses (e.g., 10, 25, 50 mg/kg) once daily for a period of 2-3 weeks. A control group receives the vehicle alone. Tumor volume is measured every 2-3 days using calipers, and body weight is recorded. At the end of the study, the mice are euthanized, and tumors are excised and weighed. The efficacy of the compound is evaluated by comparing tumor growth curves and final tumor weights between treated and control groups. Tumor tissues may be collected for histological analysis and biomarker studies to assess the compound's effects on S100B and downstream signaling pathways. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties for Heptamidine dimethanesulfonate are not extensively reported in the available literature. The compound has a molecular weight of 560.68 and is soluble in DMSO (100 mg/mL) and water (5 mg/mL). It is formulated for in vivo administration as a homogeneous suspension in CMC-Na. Specific pharmacokinetic parameters such as half-life, volume of distribution, clearance, and oral bioavailability have not been determined experimentally. The compound's metabolism is likely to involve hepatic cytochrome P450 enzymes. The compound's elimination route is unknown. Further studies are needed to fully characterize the pharmacokinetic profile of this compound. The compound's in vivo activity would depend on its ability to reach target tissues in sufficient concentrations.
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| Toxicity/Toxicokinetics |
Toxicological data for Heptamidine dimethanesulfonate is limited, as it is a research chemical. Standard safety precautions should be observed when handling this compound. No specific toxicity studies, such as acute or chronic toxicity in animal models, have been detailed in the public domain. The compound's selectivity for S100B-expressing melanoma cells suggests that it may have a favorable safety profile. However, as with all research chemicals, it should be handled with care, using appropriate personal protective equipment and following institutional safety guidelines. The compound is not approved for clinical use and should only be used in preclinical research settings.
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| References | |
| Additional Infomation |
Heptamidine dimethanesulfonate is a research tool for studying the role of S100B in melanoma. It selectively kills S100B-expressing melanoma cells. It also inhibits Trypanosoma brucei. It is not approved for clinical use.
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| Molecular Formula |
C23H36N4O8S2
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|---|---|
| Molecular Weight |
560.683943748474
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| Exact Mass |
560.197
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| CAS # |
161374-55-6
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| Related CAS # |
Heptamidine;94345-47-8
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| PubChem CID |
146047121
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| Appearance |
Off-white to light yellow solid powder
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
37
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| Complexity |
494
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CS(=O)(=O)O.CS(=O)(=O)O.C1=CC(=CC=C1C(=N)N)OCCCCCCCOC2=CC=C(C=C2)C(=N)N
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| InChi Key |
VJPVVWMWVOBCIC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H28N4O2.2CH4O3S/c22-20(23)16-6-10-18(11-7-16)26-14-4-2-1-3-5-15-27-19-12-8-17(9-13-19)21(24)25;2*1-5(2,3)4/h6-13H,1-5,14-15H2,(H3,22,23)(H3,24,25);2*1H3,(H,2,3,4)
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| Chemical Name |
4-[7-(4-carbamimidoylphenoxy)heptoxy]benzenecarboximidamide;methanesulfonic acid
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~62.5 mg/mL (~111.47 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.71 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 20.8 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: ≥ 2.08 mg/mL (3.71 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 20.8 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: ≥ 2.08 mg/mL (3.71 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 | 1.7835 mL | 8.9177 mL | 17.8355 mL | |
| 5 mM | 0.3567 mL | 1.7835 mL | 3.5671 mL | |
| 10 mM | 0.1784 mL | 0.8918 mL | 1.7835 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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