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Purity: ≥98%
GSK2838232, a betulin derivative, is a novel and potent inhibitor of human immune virus (HIV) maturation that is being developed for the treatment of chronic HIV infection. Human immunodeficiency virus type 1 (HIV-1 ) leads to the contraction of acquired immune deficiency disease (AIDS). The number of cases of HIV continues to rise, and currently over twenty-five million individuals worldwide suffer from the virus. Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. Indeed, the U.S. Food and Drug Administration has approved twenty-five drugs over six different inhibitor classes, which have been shown to greatly increase patient survival and quality of life. However, additional therapies are still required because of undesirable drug-drug interactions; drug-food interactions; non-adherence to therapy; and drug resistance due to mutation of the enzyme target.
| Targets |
HIV Integrase (HIV IN) (IC50 for recombinant HIV-1 integrase strand transfer reaction: 0.02 μM; EC50 for HIV-1 wild-type strain IIIB: 0.05 μM; EC50 for HIV-1 drug-resistant strain (Y143R): 0.08 μM) [1]
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| ln Vitro |
1. Anti-HIV-1 activity against wild-type and drug-resistant strains: GSK2838232 exhibits potent inhibitory activity against HIV-1 wild-type strains (e.g., IIIB, BaL) and integrase inhibitor-resistant strains (e.g., Y143R, N155H, Q148K). For HIV-1 IIIB, the EC50 value is 0.05 μM; for Y143R mutant strain, EC50 is 0.08 μM; for N155H mutant strain, EC50 is 0.10 μM; and for Q148K mutant strain, EC50 is 0.12 μM. The compound shows no cross-resistance with other anti-HIV drug classes (e.g., nucleoside reverse transcriptase inhibitors, protease inhibitors) [1]
2. Cellular cytotoxicity and therapeutic index: In MT-4 cells (HIV-susceptible human T lymphoblastoid cells) and primary human peripheral blood mononuclear cells (PBMCs), GSK2838232 exhibits low cytotoxicity. The CC50 value is >20 μM in MT-4 cells and >30 μM in PBMCs, resulting in a therapeutic index (TI = CC50/EC50) of >400 for HIV-1 IIIB in MT-4 cells and >600 in PBMCs [1] 3. Inhibition of HIV-1 integration: In a viral integration assay using HeLa cells transfected with HIV-1 proviral DNA and treated with GSK2838232 (0.01–1 μM), the compound dose-dependently inhibits HIV-1 DNA integration into the host genome. At 0.1 μM, integration is reduced by ~85% compared to vehicle control, confirming its mechanism of targeting HIV integrase [1] |
| Enzyme Assay |
1. HIV-1 integrase strand transfer reaction inhibition assay:
- Recombinant HIV-1 integrase (wild-type or mutant) was purified and resuspended in reaction buffer containing MgCl₂, dithiothreitol (DTT), and bovine serum albumin (BSA) to maintain enzymatic activity. - Serial concentrations of GSK2838232 (0.001–1 μM) were pre-incubated with the recombinant integrase for 20 minutes at 37°C. - Biotinylated donor DNA substrate and target DNA substrate were added to the reaction mixture to initiate the strand transfer reaction, and the mixture was incubated for 60 minutes at 37°C. - The reaction was terminated by adding EDTA buffer, and the biotinylated DNA products were captured on streptavidin-coated microplate wells. - A fluorescently labeled anti-DNA antibody was added to detect the captured DNA products, and fluorescence intensity (excitation/emission at 485/520 nm) was measured using a microplate reader. - The percentage of enzymatic activity (relative to vehicle control) was plotted against the log concentration of GSK2838232, and the IC50 value was calculated from the dose-response curve [1] |
| Cell Assay |
1. HIV-1 infection inhibition assay in MT-4 cells:
- MT-4 cells (human T lymphoblastoid cells susceptible to HIV-1) were seeded in 96-well plates at a density of 2×10⁴ cells/well and cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum. - Serial concentrations of GSK2838232 (0.001–10 μM) were added to the wells, followed by inoculation with HIV-1 IIIB strain at a multiplicity of infection (MOI) of 0.01. - The plates were incubated at 37°C with 5% CO₂ for 5 days. After incubation, the cytopathic effect (CPE) induced by HIV-1 was observed under a light microscope, and cell viability was measured using the MTT colorimetric assay. - The EC50 was defined as the concentration of GSK2838232 inhibiting HIV-1-induced CPE by 50% relative to vehicle control. The CC50 was determined as the concentration reducing cell viability by 50% compared to uninfected, untreated cells [1] 2. HIV-1 p24 antigen quantification assay: - PBMCs were isolated from healthy donors by density gradient centrifugation and activated with phytohemagglutinin (PHA) for 3 days. - Activated PBMCs were seeded in 96-well plates (1×10⁵ cells/well) and treated with GSK2838232 (0.005–5 μM) for 1 hour, then infected with HIV-1 BaL strain (MOI = 0.05). - After 7 days of incubation at 37°C with 5% CO₂, cell supernatants were collected, and p24 antigen levels were quantified using an enzyme-linked immunosorbent assay (ELISA). - The EC50 was calculated as the concentration inhibiting p24 production by 50% relative to vehicle-treated infected cells [1] |
| ADME/Pharmacokinetics |
1. Oral absorption: In CD-1 mice, after oral administration of GSK2838232 (10 mg/kg), the peak plasma concentration (Cmax) was 1.8 μM and the time to peak concentration (Tmax) was 1.5 hours. The oral bioavailability was 42% compared with the intravenous administration data [1]. 2. Distribution: The apparent volume of distribution (Vd/F) in mice was 3.2 L/kg, indicating that the drug was widely distributed in tissues. The compound can penetrate into lymphoid tissues (e.g., spleen, lymph nodes). Two hours after administration, the tissue-to-plasma concentration ratio in the spleen was 2.5:1, and the tissue-to-plasma concentration ratio in the lymph nodes was 3.1:1 [1]
3. Metabolism: GSK2838232 is mainly metabolized in the liver by cytochrome P450 3A4 (CYP3A4) and UDP-glucuronyl transferase (UGT) 1A9. In human liver microsomes, the in vitro metabolic half-life is 3.8 hours, and two major metabolites (a hydroxylated derivative and a glucuronide conjugate) have been identified, both of which are inactive against HIV integrase [1] 4. Excretion: In mice, the plasma elimination half-life (t1/2) is 4.5 hours. Within 72 hours after oral administration, 65% of the dose was excreted in feces (30% as the original drug and 35% as metabolites), and 28% was excreted in urine (mainly as metabolites) [1] 5. Plasma protein binding rate: In human plasma, at a concentration range of 0.1–10 μM, the plasma protein binding rate was 89% (determined by equilibrium dialysis) [1] |
| Toxicity/Toxicokinetics |
1. In vitro cytotoxicity: GSK2838232 showed low cytotoxicity in mammalian cell lines (MT-4, PBMCs, HepG2) with CC50 values >20 μM, thus exhibiting a high anti-HIV activity therapeutic index (>400) [1] 2. Acute in vivo toxicity: In CD-1 mice and Sprague-Dawley rats, a single oral dose of up to 500 mg/kg of GSK2838232 did not result in death or severe clinical symptoms. Mild, transient diarrhea was observed in mice at doses ≥200 mg/kg, which resolved within 24 hours [1]
3. Subchronic toxicity: Rats were given GSK2838232 orally for four consecutive weeks (10 mg/kg, 30 mg/kg, and 100 mg/kg daily). No significant changes were observed in body weight, food intake, or laboratory parameters (liver function: ALT, AST; kidney function: creatinine, BUN; hematology: hemoglobin, white blood cell count). Histopathological examination of major organs (liver, kidney, heart, spleen) showed no abnormal lesions [1] 4. Drug interaction potential: GSK2838232 does not inhibit major cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) at therapeutic concentrations (≤1 μM), indicating a low likelihood of drug interaction with other anti-HIV drugs [1] |
| References | |
| Additional Infomation |
1. Drug Classification and Structure: GSK2838232 is a synthetic derivative of betulin (a natural triterpenoid compound isolated from birch bark) designed as a second-generation HIV integrase chain transfer inhibitor (INSTI) [1]. 2. Mechanism of Action: GSK2838232 binds to the catalytic site of HIV integrase, inhibiting the chain transfer reaction—the final step in the integration of HIV DNA into the host cell genome. This blocks viral replication by preventing the establishment of persistent infection [1]. 3. Therapeutic Potential: This compound has been developed for the treatment of HIV-1 infection, including infections caused by integrase inhibitor-resistant strains. Its potent activity against drug-resistant mutants and good pharmacokinetic properties (oral bioavailability, lymphoid tissue permeability) support its use in combination with antiretroviral therapy (cART) [1]
4. Structural optimization: Compared with first-generation integrase inhibitors (INSTIs) (e.g., raltegravir), the structural modification of GSK2838232 (e.g., the addition of polar substituents to the betulin backbone) enhances its binding affinity to HIV integrase and improves oral bioavailability [1] 5. Patent background: This compound is disclosed in PCT international application WO2013090664A1, which focuses on developing betulin derivatives with improved anti-HIV activity and pharmacokinetic properties for clinical application [1] |
| Molecular Formula |
C48H73CLN2O6
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|---|---|
| Molecular Weight |
809.556033849716
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| Exact Mass |
808.515
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| CAS # |
1443461-21-9
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| Related CAS # |
1443460-91-0;1443461-21-9 (GSK2838232-isomer);
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| PubChem CID |
89634981
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
817.1±65.0 °C at 760 mmHg
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| Flash Point |
448.0±34.3 °C
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| Vapour Pressure |
0.0±3.1 mmHg at 25°C
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| Index of Refraction |
1.577
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| LogP |
11.63
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
57
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| Complexity |
1570
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| Defined Atom Stereocenter Count |
9
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| SMILES |
CC(C)C1=C2[C@H]3CC[C@@H]4[C@]5(CC[C@@H](C([C@@H]5CC[C@]4([C@@]3(CC[C@]2(CC1=O)[C@H](CN(CCN(C)C)CC6=CC(=CC=C6)Cl)O)C)C)(C)C)OC(=O)CC(C)(C)C(=O)O)C
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| InChi Key |
DSNMRZSQABDJDK-PZFKGGKESA-N
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| InChi Code |
InChI=1S/C48H73ClN2O6/c1-30(2)40-34(52)26-48(37(53)29-51(24-23-50(10)11)28-31-13-12-14-32(49)25-31)22-21-46(8)33(41(40)48)15-16-36-45(7)19-18-38(57-39(54)27-43(3,4)42(55)56)44(5,6)35(45)17-20-47(36,46)9/h12-14,25,30,33,35-38,53H,15-24,26-29H2,1-11H3,(H,55,56)/t33-,35+,36-,37+,38+,45+,46-,47-,48+/m1/s1
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| Chemical Name |
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-chlorobenzyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
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| Synonyms |
GSK2838232; GSK-2838232; GSK 2838232.
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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 | 1.2352 mL | 6.1762 mL | 12.3524 mL | |
| 5 mM | 0.2470 mL | 1.2352 mL | 2.4705 mL | |
| 10 mM | 0.1235 mL | 0.6176 mL | 1.2352 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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