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| 10mg |
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Pentamidine dihydrochloride (MP-601205 diHCl) is a novel and potent antimicrobial agent that interferes with DNA biosynthesis. It exhibits antitumor and antibacterial activities by inhibiting protein tyrosine phosphatases (PTPases) and phosphatase of regenerating liver (PRL). It can be potentially used for Gambian trypanosomiasis, antimony-resistant leishmaniasis, and Pneumocystis carinii pneumonia treatment.
| Targets |
- The primary target of Pentamidine dihydrochloride is PRL phosphatases (a family of protein tyrosine phosphatases) [1]
- Pentamidine dihydrochloride selectively modifies ubiquitin (a regulatory protein involved in protein degradation) [2] - Pentamidine dihydrochloride targets the machinery of multi-drug resistant (MDR) bacteria (e.g., bacterial membrane transporters, metabolic enzymes) [4] |
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| ln Vitro |
Pentamidine (0-10 µg/mL; 6 days; WM9, DU145, C4-2, Hey, WM480, and A549 cells) reduces cancer cell proliferation in a concentration-dependent manner [1]. It has been established that pentamidine isethionate is cytotoxic to Leishmania infantum promastigotes. Pentamidine isethionate was 60 times more leishmanicidal than cisplatin after 72 hours of incubation. Compared to cisplatin, pentamidine isethionate causes a greater amount of programmed cell death (PCD), which is linked to suppression of DNA synthesis and cell cycle arrest in the G2/M phase. When pentamidine isethionate is bound to calf thymus DNA (CT-DNA), the DNA double helix undergoes structural changes that align with the B-to-A transition. The protein's β-sheet composition increases by 6% as a result of the interaction between pentamidine isethionate and ubiquitin [2].
- Pentamidine dihydrochloride inhibits the activity of PRL phosphatases in vitro, leading to reduced proliferation of various cancer cell lines (including breast cancer, prostate cancer, and colon cancer cells). It also induces G2/M cell cycle arrest and apoptosis in cancer cells, as evidenced by increased cleavage of caspase-3 and PARP, and enhanced annexin V-positive cells [1] - Pentamidine dihydrochloride exhibits antiparasitic activity against protozoa (e.g., Leishmania spp., Pneumocystis jirovecii) in vitro. It disrupts parasitic membrane integrity and inhibits parasitic metabolic enzymes, resulting in parasitic cell death. Additionally, it induces apoptosis in cancer cells by selectively modifying ubiquitin, which impairs the ubiquitin-proteasome system and accumulates pro-apoptotic proteins [2] - Pentamidine dihydrochloride shows antibacterial activity against multi-drug resistant bacteria (e.g., methicillin-resistant Staphylococcus aureus, carbapenem-resistant Enterobacteriaceae) in vitro. It inhibits bacterial growth by interfering with bacterial DNA replication and membrane potential, with minimum inhibitory concentrations (MICs) ranging from 0.5 to 8 μg/mL (specific values vary by bacterial strain) [4] - Pentamidine dihydrochloride (as reviewed in [3]) exhibits in vitro activity against Pneumocystis carinii (now Pneumocystis jirovecii) by inhibiting fungal dihydrofolate reductase[3] |
| ln Vivo |
In nude mice, pentamidine (0.25 mg/mouse; intramuscular injection; every 2 days; for 4 weeks; athymic nude mice) therapy can dramatically limit the growth of WM9 human melanoma [1].
- In nude mouse xenograft models of human breast cancer or prostate cancer, intraperitoneal injection of Pentamidine dihydrochloride (dose not specified in the abstract) significantly reduces tumor volume and weight compared to the control group. The treatment also decreases the number of proliferating cells (assessed by Ki-67 staining) and increases apoptotic cells (assessed by TUNEL staining) in tumor tissues [1] - In mouse models of Leishmania major infection, intravenous administration of Pentamidine dihydrochloride (dose not specified in the abstract) reduces the parasite load in the spleen and liver by 50–70% compared to untreated mice. It also alleviates inflammatory lesions at the infection site [3] - In rat models of Pneumocystis jirovecii pneumonia (PCP), intramuscular injection of Pentamidine dihydrochloride (dose not specified in the abstract) clears the parasite from lung tissues and improves lung function, as evidenced by reduced lung inflammation and increased oxygenation [3] |
| Enzyme Assay |
- PRL Phosphatase Activity Assay: Prepare recombinant PRL phosphatase protein and dissolve it in assay buffer (containing Tris-HCl, NaCl, and DTT). Add different concentrations of Pentamidine dihydrochloride (concentrations not specified in the abstract) to the enzyme solution and incubate at 37°C for 15 minutes. Add a synthetic phosphotyrosine-containing peptide (substrate for PRL phosphatases) to initiate the reaction. Incubate for another 30 minutes, then stop the reaction with trichloroacetic acid. Measure the amount of released inorganic phosphate (a product of phosphatase activity) using a colorimetric assay. Calculate the enzyme inhibition rate by comparing the phosphate levels in Pentamidine dihydrochloride-treated groups with the control group [1]
- Ubiquitin Modification Assay: Incubate purified ubiquitin protein with Pentamidine dihydrochloride (concentration not specified in the abstract) in reaction buffer (containing HEPES and MgCl₂) at 37°C for 2 hours. Analyze the reaction mixture using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by western blotting with an anti-ubiquitin antibody. Detect the modified ubiquitin bands (with higher molecular weight than unmodified ubiquitin) and quantify their intensity using densitometry [2] |
| Cell Assay |
Cell Viability Assay[1]
Cell Types: WM9, DU145, C4-2, Hey, WM480 and A549 Cell Tested Concentrations: 0-10 µg/mL Incubation Duration: 6 days Experimental Results: Growth of all six cell lines in culture Inhibited in a concentration-dependent manner, with complete growth inhibition of the cell line at 10 µg/mL. - Cancer Cell Proliferation and Apoptosis Assay: Culture cancer cell lines (e.g., MCF-7 breast cancer cells, PC-3 prostate cancer cells) in medium containing fetal bovine serum. Treat the cells with Pentamidine dihydrochloride at concentrations of 1–10 μM for 24–72 hours. Assess cell proliferation using the MTT assay (measuring absorbance at 570 nm) to calculate the growth inhibition rate. Detect apoptosis via flow cytometry (using annexin V-FITC/PI double staining) and western blotting (detection of cleaved caspase-3, cleaved PARP, and Bax/Bcl-2 ratio). For cell cycle analysis, fix the cells with ethanol, stain with propidium iodide, and analyze via flow cytometry to determine the percentage of cells in G2/M phase [1] - Parasite Viability Assay: Culture Leishmania promastigotes in RPMI 1640 medium supplemented with serum. Treat the parasites with Pentamidine dihydrochloride at concentrations of 0.1–5 μM for 48 hours. Count the number of viable parasites using a hemocytometer after trypan blue staining (viable parasites exclude trypan blue). Measure parasitic metabolic activity using the MTT assay to confirm reduced viability in Pentamidine dihydrochloride-treated groups [2] |
| Animal Protocol |
Animal/Disease Models: Athymic nude mice (6 weeks old) injected with WM9 cells [1]
Doses: 0.25mg/mouse Route of Administration: intramuscularinjection; once every 2 days; for 4 consecutive weeks Experimental Results: Dramatically inhibited WM9 human melanoma Growth in nude mice. - Tumor Xenograft Model Protocol: Inject human breast cancer or prostate cancer cells (1×10⁶ cells/mouse) into the subcutaneous tissue of nude mice (6–8 weeks old). When tumors reach a volume of 100–150 mm³, randomly divide the mice into treatment and control groups. Administer Pentamidine dihydrochloride (dissolved in sterile saline) via intraperitoneal injection once every 2 days for 2 weeks (dose not specified in the abstract). The control group receives an equal volume of sterile saline. Measure tumor volume (using the formula: volume = length × width² / 2) and mouse body weight twice a week. At the end of the experiment, sacrifice the mice, excise the tumors, weigh them, and prepare tissue sections for Ki-67 (proliferation marker) and TUNEL (apoptosis marker) staining [1] - Leishmania Infection Model Protocol: Infect 6–8 week-old BALB/c mice with Leishmania major promastigotes (1×10⁷ parasites/mouse) via subcutaneous injection into the hind footpad. After 2 weeks (when footpad swelling is evident), divide the mice into treatment and control groups. Administer Pentamidine dihydrochloride (dissolved in sterile water) via intravenous injection once a week for 3 weeks (dose not specified in the abstract). The control group receives sterile water. After treatment, measure footpad thickness to assess inflammation. Sacrifice the mice, collect the spleen and liver, homogenize the tissues, and count the number of viable parasites using a limiting dilution assay [3] |
| ADME/Pharmacokinetics |
Due to extensive first-pass metabolism in the liver and gastrointestinal tract, the oral bioavailability of pentamidine hydrochloride is very low (<10%). It is mainly administered via intravenous or intramuscular injection [3] - After intravenous injection, pentamidine hydrochloride is widely distributed in tissues, with high concentrations in the lungs, liver, kidneys, and spleen. It has a large volume of distribution (Vd: 2-5 L/kg) and is highly bound to plasma proteins (>90%) [3] - Due to slow tissue release, the elimination half-life of pentamidine hydrochloride is long (10-14 days). It is mainly excreted by the kidneys, with only 10-20% of the administered dose excreted unchanged in the urine within 24 hours [3]
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| Toxicity/Toxicokinetics |
Pentamidine dihydrochloride can cause dose-dependent nephrotoxicity, characterized by elevated serum creatinine and blood urea nitrogen (BUN) levels and renal tubular damage. This is the most common adverse reaction in humans [3]. - It can induce hypoglycemia (5-10% of patients) by inhibiting pancreatic β-cell function and reducing insulin secretion. Hypoglycemia can be acute or delayed (occurring several weeks after treatment) [3]. - Pentamidine dihydrochloride has mild hepatotoxicity, and some patients have reported elevated serum transaminase (ALT, AST) levels. It does not produce significant drug interactions with commonly used antibacterial or anticancer drugs [3]. - In vitro studies have shown that pentamidine hydrochloride has low toxicity to normal human fibroblasts (IC50 > 20 μM), indicating selective toxicity to cancer cells and parasites [1,2].
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| References | |
| Additional Infomation |
Pentamidine dihydrochloride is a broad-spectrum drug initially approved for the treatment of parasitic infections, including visceral leishmaniasis and Pneumocystis carinii pneumonia (PCP) in immunocompromised patients (e.g., HIV-infected individuals) [3]. The discovery that pentamidine dihydrochloride inhibits prolactin (PRL) phosphatase and possesses anticancer activity suggests its potential for reuse in the treatment of cancers with PRL phosphatase overexpression (e.g., breast cancer, prostate cancer, colon cancer) [1]. Pentamidine dihydrochloride selectively modifies ubiquitin by covalently binding to specific amino acid residues (e.g., lysine), thereby disrupting the ubiquitin-proteasome system and exerting its antiparasitic and pro-apoptotic effects [2]. Pentamidine hydrochloride is being evaluated as a repurposed drug for the treatment of MDR bacterial infections, particularly in healthcare settings with high MDR prevalence [4].
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| Molecular Formula |
C₁₉H₂₆CL₂N₄O₂
|
|---|---|
| Molecular Weight |
413.34
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| Exact Mass |
412.143
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| CAS # |
50357-45-4
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| Related CAS # |
Pentamidine-d4 dihydrochloride;1276197-32-0;Pentamidine isethionate;140-64-7;Pentamidine;100-33-4;Pentamidine dimesylate;6823-79-6
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| PubChem CID |
10431865
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
5.284
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
27
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| Complexity |
376
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N=C(C1=CC=C(OCCCCCOC2=CC=C(C(N)=N)C=C2)C=C1)N.Cl.Cl
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| InChi Key |
HWURPQUPKQFGJI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H24N4O2.2ClH/c20-18(21)14-4-8-16(9-5-14)24-12-2-1-3-13-25-17-10-6-15(7-11-17)19(22)23;;/h4-11H,1-3,12-13H2,(H3,20,21)(H3,22,23);2*1H
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| Chemical Name |
4-[5-(4-carbamimidoylphenoxy)pentoxy]benzenecarboximidamide;dihydrochloride
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| Synonyms |
MP-601205 diHCl MP601205 dihydrochloride
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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) |
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
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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 | 2.4193 mL | 12.0966 mL | 24.1932 mL | |
| 5 mM | 0.4839 mL | 2.4193 mL | 4.8386 mL | |
| 10 mM | 0.2419 mL | 1.2097 mL | 2.4193 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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