4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-1,3-benzodiazol-2-yl}butanoic acid hydrochloride

• ChemBase ID: 72575
• Molecular Formular: C16H22Cl3N3O2
• Molecular Mass: 394.72378
• Monoisotopic Mass: 393.07776
• SMILES: c1c(cc2c(c1)n(c(n2)CCCC(=O)O)C)N(CCCl)CCCl.Cl
• Canonical SMILES: ClCCN(c1ccc2c(c1)nc(n2C)CCCC(=O)O)CCCl.Cl
• InChI: InChI=1S/C16H21Cl2N3O2.ClH/c1-20-14-6-5-12(21(9-7-17)10-8-18)11-13(14)19-15(20)3-2-4-16(22)23;/h5-6,11H,2-4,7-10H2,1H3,(H,22,23);1H
• InChIKey: ZHSKUOZOLHMKEA-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-1,3-benzodiazol-2-yl}butanoic acid hydrochloride
• IUPAC Traditional name: 4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-1,3-benzodiazol-2-yl}butanoic acid hydrochloride; bendamustine hydrochloride
• Synonyms: Bendamustine hydrochloride; 5-[Bis(2-chloroethyl)-amino]-1-methyl-1H-benzimidazole-2-butanoic Acid Hydrochloride; Cytostasan; 4-(5-(bis(2-chloroethyl)amino)-1-methyl-benzimidazol-2-yl)butyric acid hydrochloride; Ribomustin; Treanda; SDX-105; Bendamustine Hydrochloride

Database IDs

• CAS Number: 97832-05-8; 3543-75-7
• PubChem SID: 162037500
• PubChem CID: 77082

CALCULATED PROPERTIES

• Acid pKa: 4.3772397
• H Acceptors: 4
• H Donor: 1
• LogD (pH = 5.5): 1.7300161
• LogD (pH = 7.4): 0.95016146
• Log P: 1.6649948
• Molar Refractivity: 92.9154 cm^3
• Polarizability: 36.44468 Å^3
• Polar Surface Area: 58.36 Å^2
• Rotatable Bonds: 9
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO; Hot Water; Methanol
• Apperance: Off-White to Light Tan Solid
• Melting Point: 149-151°C

Safety Information

• Storage Condition: -20°C; -20°C Freezer

Pharmacology Properties

• Mechanism of Action: Acts as an alkylating agent causing intra-strand and inter-strand cross-links between DNA bases

Product Information

• Purity: 97%
• Salt Data: HCl; Hydrochloride
• Application(s): Used in the treatment of chronic lymphocytic leukemias (CLL) and lymphomas

DETAILS

Selleck Chemicals - S1212

Research Area

• Description: Cancer

Biological Activity

• Description: Bendamustine HCL (Ribomustin, Treanda, SDX-105) is a DNA-damaging agent with IC50 of 50 μM.
• Targets: DNA
• IC50: 50 μM ^[1]
• In Vitro: DNA single- and double-strand breaks caused by Bendamustine are more extensive and significantly more durable than those caused by cyclophosphamide, cisplatinum, or carmustine. Bendamustine specifically regulates, transcriptionally and posttranslationally, genes involved in apoptosis, DNA repair, and mitotic checkpoints. Bendamustine uniquely regulates DNA repair pathways in non–Hodgkin's lymphoma cells compared with other alkylators. Bendamustine inhibits mitotic checkpoints and induces mitotic catastrophe. Treatment with Bendamustine results in a 60% to 80% down-regulation of the mRNA expression of all three of these genes [polo-like kinase 1 (PLK-1), Aurora Kinase A, and cyclin B1] in SU-DHL-9 cells. Twenty-six percent of the Bendamustine-treated MCF-7/ADR cells showed micronucleation compared with only 6% in DMSO control cells. ^[1] Using Bendamustine alone in concentrations from 1 μg/mL to 50 μg/mL, a dose- and time-dependent manner of cytotoxicity from 30.4% to 94.8% after 48 hours could be observed. The LD50 for untreated and pretreated CLL cells is 7.3 or 4.4 μg /mL, respectively. ^[2] Myeloid and breast carcinoma cell lines are resistant towards Bendamustine with the exception of HL-60 cells which exhibit an intermediate sensitivity. Bendamustine is found to have a very low clastogenic effect as compared with equimolar doses of lomustine. ^[3]
• In Vivo: A single dose of Bendamustine at 25 mg/kg demonstrates significant activity in all three tumor lines (DoHH-2, Granta 519 and RAMOS). DoHH-2 is the most sensitive, with 30% ORR and a 69% inhibition in tumor growth. Growth of Granta 519 and RAMOS is also inhibited by Bendamustine (%TGI of 74% and 81%, respectively), and the effect is more durable in Granta 519 (%TGD of 124%) than for DoHH-2 or RAMOS (69% and 43%, respectively). ^[4]
• Clinical Trials: Bendamustine HCl has entered in a phase II clinical trial in the treatment of ovarian cancer.
• Features: Bendamustine is approved for the treatment of multiple hematologic tumors, including indolent and rituximab-resistant NHL.

Combination Therapy

• Description: Bendamustine in combination with either doxorubicin or mitoxantrone causes antagonistic effects on disruption of mitochondrial membrane potential as well as on the rate of apoptosis. In contrast the combination of Bendamustine with cladribine acts synergistically on these parameters. ^[5] The combination of Bendamustine with Fludarabine leads to a highly synergistic effect in inducing apoptosis, which is 150% higher than expected for Bendamustine plus fludarabine. ^[2] Combination of navitoclax and Bendamustine has a greater than additive response in all three models tested (DoHH-2, Granta 519 and RAMOS model). Tumor growth inhibition is significantly increased to 91%, 99% and 95% for DoHH-2, Granta 519 and RAMOS, respectively. Bendamustine treatment alone has little to no effect on caspase 3 cleavage in Granta 519 tumors. However, addition of navitoclax induces a significant increase in cleaved caspase 3 staining at 24 hours. ^[4] Bendamustine plus Bortezomib and Rituximab has entered in phase II clinical trial in the treatment of lymphoma.

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: SU-DHL-1 and SU-DHL-9 cells
• Concentrations: 0-100 μM
• Incubation Time: 72 hours
• Methods: SU-DHL-1 and SU-DHL-9 cells are preincubated for 30 minutes with either 6 mM methoxyamine or 50 μM O6-benzylguanine, inhibitors of Ape-1 base excision repair enzyme, or alkylguanyl transferase enzyme, respectively. The cells are then exposed to various concentrations of Bendamustine for 72 hours. Cytotoxicity is evaluated by the MTT viability assay and an IC50 is determined as the drug concentration that inhibited by 50% the viability value of the untreated control. Analyses are done.
• Protocol: Animal Study ^[5]
• Animal Models: C.B.-17 scid mice bearing DoHH-2, Granta 519 or C.B.-17 scid-bg mice bearing SuDHL-4, RAMOS
• Formulation: Control
• Doses: 25 mg/kg
• Administration: Administered via i.v.

References

• References: [1] Leoni LM, et al. Clin Cancer Res. 2008, 14(1), 309-317.
• References: [2] Schwänen C, et al. Leukemia. 2002, 16(10), 2096-2105.
• References: [3] Konstantinov SM, et al. J Cancer Res Clin Oncol. 2002, 128(5), 271-278.
• References: [4] Ackler S, et al. Br J Pharmacol. 2012.
• References: [5] Chow KU, et al. Biochem Pharmacol. 2003, 66(5), 711-724.

Toronto Research Chemicals - B132500

Used as an anticancer drug.

REFERENCES

• Leoni LM, et al. Clin Cancer Res. 2008, 14(1), 309-317.
• Schwänen C, et al. Leukemia. 2002, 16(10), 2096-2105.
• Konstantinov SM, et al. J Cancer Res Clin Oncol. 2002, 128(5), 271-278.
• Ackler S, et al. Br J Pharmacol. 2012.
• Chow KU, et al. Biochem Pharmacol. 2003, 66(5), 711-724.
• Bremer, K., et al.: Tumordiagn. Ther., 17, 1 (1996)
• Barman Balfour, J.A., et al.: Drugs, 61, 631 (1996)
• 2. Bagchi S (August 2007). "Bendamustine for advanced sarcoma". Lancet Oncol. 8 (8): 674.
• 1. Kath R, Blumenstengel K, Fricke HJ, Ho"ffken K (January 2001). "Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia". J. Cancer Res. Clin. Oncol. 127 (1): 48?4.