Bendamustine HCl
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MedKoo CAT#: 200470

CAS#: 3543-75-7 (HCl)

Description: Bendamustine hydrochloride is the hydrochloride salt of bendamustine, a bifunctional mechlorethamine derivative with alkylator and antimetabolite activities. Bendamustine possesses three active moieties: an alkylating group; a benzimidazole ring, which may act as a purine analogue; and a butyric acid side chain. Although its exact mechanism of action is unknown, this agent appears to act primarily as an alkylator. Bendamustine metabolites alkylate and crosslink macromolecules, resulting in DNA, RNA and protein synthesis inhibition, and, subsequently, apoptosis. In October 2008, the FDA granted further approval to market Treanda for the treatment of indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.


Chemical Structure

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Bendamustine HCl
CAS# 3543-75-7 (HCl)

Theoretical Analysis

MedKoo Cat#: 200470
Name: Bendamustine HCl
CAS#: 3543-75-7 (HCl)
Chemical Formula: C16H22Cl3N3O2
Exact Mass:
Molecular Weight: 394.72
Elemental Analysis: C, 48.68; H, 5.62; Cl, 26.95; N, 10.65; O, 8.11

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2.0g USD 750.0 Same day
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10.0g USD 2250.0 Same day
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Related CAS #: 3543-75-7 (HCl)   16506-27-7 (free base)    

Synonym: SDX105; SDX 105; SDX-105; DD6304600; Bendamustine HCl; Bendamustine hydrochloride; Brand name: Treanda.

IUPAC/Chemical Name: 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid hydrochloride

InChi Key: ZHSKUOZOLHMKEA-UHFFFAOYSA-N

InChi Code: 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

SMILES Code: O=C(O)CCCC1=NC2=CC(N(CCCl)CCCl)=CC=C2N1C.[H]Cl

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: soluble in DMSO, not soluble in water.

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Bendamustine hydrochloride (SDX-105), a purine analogue, is a DNA cross-linking agent.
In vitro activity: PT-BEN (post-transplant bendamustine) is lymphodepleting, relatively spares the myeloid compartment and significantly increases MDSCs. This study therefore further investigated the differential effects of BEN on these subsets in vitro. MDSCs were generated from naïve BM in the presence of increasing concentrations of BEN. After 3 days in culture, >90% of cells were CD11b+Gr-1+ (Supplemental Figure 7), with no significant differences between groups. MDSCs generated with higher concentrations of BEN were significantly more suppressive than those generated with lower concentrations (Figure 7A). Reference: Br J Haematol. 2016 Jul; 174(1): 102–116. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917459/
In vivo activity: Therefore, this study evaluated the two host cDC subsets in BEN+TBI (bendamustine combined with total body irradiation) vs. CY+TBI (cyclophosphamide with total body irradiation) conditioning. Representative flow plots of cDC1 and cDC2 populations on day 0 are depicted in Figure 3A, demonstrating differences between BEN+TBI and CY+TBI. The CD8α-SIRPα- DCs are considered pre-cDCs that have not yet committed to either of the two cDC lineages. Quantification of these flow cytometry plots shows significantly more CD8α+ cDC1s with BEN+TBI conditioning than with CY+TBI (Figure 3B), and significantly fewer SIRPα+ cDC2s (Figure 3D) on day +1. The absolute numbers of CD8α+ cDC1s (Figure 3C) and SIRPα+ cDC2s (Figure 3E) were not different on day 0. Given that total cDCs have been reported to exacerbate GvHD, whereas CD8α+ cDC1s are highly effective suppressors of GvHD, this study evaluated the ratio of CD8α+cDC1 to SIRPα+cDC2 in each mouse conditioned with BEN+TBI or CY+TBI. This study found that the ratio of favorable cDC1s to unfavorable cDC2s was significantly higher in BEN+TBI mice on days 0 and +1 (Figure 3F). Reference: Front Immunol. 2020; 11: 1410. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378358/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 72.49 183.65
Ethanol 78.0 197.61
Water 43.94 111.32

Preparing Stock Solutions

The following data is based on the product molecular weight 394.72 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Stokes J, Hoffman EA, Zeng Y, Larmonier N, Katsanis E. Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation. Br J Haematol. 2016 Jul;174(1):102-16. doi: 10.1111/bjh.14034. Epub 2016 Mar 31. PMID: 27030315; PMCID: PMC4917459. 2. Leoni LM, Bailey B, Reifert J, Bendall HH, Zeller RW, Corbeil J, Elliott G, Niemeyer CC. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res. 2008 Jan 1;14(1):309-17. doi: 10.1158/1078-0432.CCR-07-1061. PMID: 18172283. 3. Molina MS, Stokes J, Hoffman EA, Eremija J, Zeng Y, Simpson RJ, Katsanis E. Bendamustine Conditioning Skews Murine Host DCs Toward Pre-cDC1s and Reduces GvHD Independently of Batf3. Front Immunol. 2020 Jul 16;11:1410. doi: 10.3389/fimmu.2020.01410. PMID: 32765499; PMCID: PMC7378358. 4. Stokes J, Hoffman EA, Molina MS, Kummet N, Simpson RJ, Zeng Y, Katsanis E. Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia. Oncoimmunology. 2020 Apr 30;9(1):1758011. doi: 10.1080/2162402X.2020.1758011. PMID: 32391190; PMCID: PMC7199810.
In vitro protocol: 1. Stokes J, Hoffman EA, Zeng Y, Larmonier N, Katsanis E. Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation. Br J Haematol. 2016 Jul;174(1):102-16. doi: 10.1111/bjh.14034. Epub 2016 Mar 31. PMID: 27030315; PMCID: PMC4917459. 2. Leoni LM, Bailey B, Reifert J, Bendall HH, Zeller RW, Corbeil J, Elliott G, Niemeyer CC. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res. 2008 Jan 1;14(1):309-17. doi: 10.1158/1078-0432.CCR-07-1061. PMID: 18172283.
In vivo protocol: 1. Molina MS, Stokes J, Hoffman EA, Eremija J, Zeng Y, Simpson RJ, Katsanis E. Bendamustine Conditioning Skews Murine Host DCs Toward Pre-cDC1s and Reduces GvHD Independently of Batf3. Front Immunol. 2020 Jul 16;11:1410. doi: 10.3389/fimmu.2020.01410. PMID: 32765499; PMCID: PMC7378358. 2. Stokes J, Hoffman EA, Molina MS, Kummet N, Simpson RJ, Zeng Y, Katsanis E. Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia. Oncoimmunology. 2020 Apr 30;9(1):1758011. doi: 10.1080/2162402X.2020.1758011. PMID: 32391190; PMCID: PMC7199810.

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1: Alrifai T, Grant Szymanski K, Venugopal P, Mahon B, Okwuosa T, Karmali R. Bendamustine and Rituximab: Complete Response in a 62-Year-Old Female with an Aggressive Lymphoma and an Ejection Fraction of 20. Chemotherapy. 2017;62(2):140-146. doi: 10.1159/000452756. Epub 2016 Dec 14. Review. PubMed PMID: 27960150.

2: Gafter-Gvili A, Polliack A. Bendamustine associated immune suppression and infections during therapy of hematological malignancies. Leuk Lymphoma. 2016;57(3):512-9. doi: 10.3109/10428194.2015.1110748. Epub 2015 Dec 23. Review. PubMed PMID: 26696321.

3: Cheson BD, Brugger W, Damaj G, Dreyling M, Kahl B, Kimby E, Ogura M, Weidmann E, Wendtner CM, Zinzani PL. Optimal use of bendamustine in hematologic disorders: Treatment recommendations from an international consensus panel - an update. Leuk Lymphoma. 2016;57(4):766-82. doi: 10.3109/10428194.2015.1099647. Epub 2015 Nov 23. Review. PubMed PMID: 26592922; PubMed Central PMCID: PMC4840280.

4: Gentile M, Vigna E, Recchia AG, Morabito L, Mendicino F, Giagnuolo G, Morabito F. Bendamustine in multiple myeloma. Eur J Haematol. 2015 Nov;95(5):377-88. doi: 10.1111/ejh.12609. Epub 2015 Jul 14. Review. PubMed PMID: 26085055.

5: Darwish M, Bond M, Hellriegel E, Robertson P Jr, Chovan JP. Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. Cancer Chemother Pharmacol. 2015 Jun;75(6):1143-54. doi: 10.1007/s00280-015-2727-6. Epub 2015 Apr 1. Review. PubMed PMID: 25829094; PubMed Central PMCID: PMC4441746.

6: Kuno M, Inoue A, Aimoto M, Nakao T, Kameda K, Yoshida M, Kanashima H, Hirai M, Yamane T. [Alleviated anemia by bendamustine in cold agglutinin disease associated with small lymphocytic lymphoma]. Rinsho Ketsueki. 2015 Feb;56(2):204-9. doi: 10.11406/rinketsu.56.204. Review. Japanese. PubMed PMID: 25765801.

7: Palumbo A, Offidani M, Patriarca F, Petrucci MT, Cavo M. Bendamustine for the treatment of multiple myeloma in first-line and relapsed-refractory settings: a review of clinical trial data. Leuk Lymphoma. 2015 Mar;56(3):559-67. doi: 10.3109/10428194.2014.915545. Epub 2014 Jun 27. Review. PubMed PMID: 24884319.

8: Haddad H, Mohammad F, Dai Q. Bendamustine-induced immune hemolytic anemia in a chronic lymphocytic leukemia patient: A case report and review of the literature. Hematol Oncol Stem Cell Ther. 2014 Dec;7(4):162-4. doi: 10.1016/j.hemonc.2014.04.001. Epub 2014 Apr 29. Review. PubMed PMID: 24785506.

9: Gil L, Kazmierczak M, Kroll-Balcerzak R, Komarnicki M. Bendamustine-based therapy as first-line treatment for non-Hodgkin lymphoma. Med Oncol. 2014 May;31(5):944. doi: 10.1007/s12032-014-0944-1. Epub 2014 Apr 22. Review. PubMed PMID: 24752517; PubMed Central PMCID: PMC4006123.

10: Ohmachi K, Maruyama D, Nisikori M, Suzuki T, Izutsu K. [Recommendation for the optimal use of bendamustine in Japan]. Rinsho Ketsueki. 2014 Mar;55(3):311-20. Review. PubMed PMID: 24681934.

11: Mitsumori T, Sueki Y, Kawashima I, Yamamoto T, Nozaki Y, Nakajima K, Kirito K. [Development of cytomegalovirus antigenemia in 3 patients with B cell lymphoma treated with bendamustine monotherapy]. Rinsho Ketsueki. 2014 Feb;55(2):239-43. Review. Japanese. PubMed PMID: 24598192.

12: Derenzini E, Zinzani PL, Cheson BD. Bendamustine: role and evidence in lymphoma therapy, an overview. Leuk Lymphoma. 2014 Jul;55(7):1471-8. doi: 10.3109/10428194.2013.842986. Epub 2014 Feb 4. Review. PubMed PMID: 24180334.

13: van der Jagt R. Bendamustine for indolent non-Hodgkin lymphoma in the front-line or relapsed setting: a review of pharmacokinetics and clinical trial outcomes. Expert Rev Hematol. 2013 Oct;6(5):525-37. doi: 10.1586/17474086.2013.841538. Review. PubMed PMID: 24125522.

14: Parker SM, Hyder MA, Fesler MJ. Bendamustine and rituximab for indolent B-cell non-hodgkin lymphoma in patients with compensated hepatitis C cirrhosis: a case series. Clin Lymphoma Myeloma Leuk. 2013 Dec;13(6):e15-7. doi: 10.1016/j.clml.2013.07.002. Epub 2013 Sep 20. Review. PubMed PMID: 24060287.

15: Gentile M, Recchia AG, Mazzone C, Vigna E, Martino M, Morabito L, Lucia E, Bossio S, De Stefano L, Granata T, Palummo A, Morabito F. An old drug with a new future: bendamustine in multiple myeloma. Expert Opin Pharmacother. 2013 Nov;14(16):2263-80. doi: 10.1517/14656566.2013.837885. Epub 2013 Sep 21. Review. PubMed PMID: 24053161.

16: Brugger W, Ghielmini M. Bendamustine in indolent non-Hodgkin's lymphoma: a practice guide for patient management. Oncologist. 2013;18(8):954-64. doi: 10.1634/theoncologist.2013-0079. Epub 2013 Jul 30. Review. PubMed PMID: 23900001; PubMed Central PMCID: PMC3755934.

17: Ogura M. Rituximab plus bendamustine for the treatment of aggressive non-hodgkin lymphoma patients with severe liver impairment. Clin Adv Hematol Oncol. 2013 Mar;11(3):188-9. Review. PubMed PMID: 23598989.

18: Vidal L, Gafter-Gvili A, Gurion R, Raanani P, Dreyling M, Shpilberg O. Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2012 Sep 12;(9):CD009045. doi: 10.1002/14651858.CD009045.pub2. Review. PubMed PMID: 22972131.

19: Hoy SM. Bendamustine: a review of its use in the management of chronic lymphocytic leukaemia, rituximab-refractory indolent non-Hodgkin's lymphoma and multiple myeloma. Drugs. 2012 Oct 1;72(14):1929-50. doi: 10.2165/11209510-000000000-00000. Review. PubMed PMID: 22950536.

20: Chang JE, Kahl BS. Bendamustine for treatment of chronic lymphocytic leukemia. Expert Opin Pharmacother. 2012 Jul;13(10):1495-505. doi: 10.1517/14656566.2012.693163. Epub 2012 Jun 5. Review. PubMed PMID: 22663160; PubMed Central PMCID: PMC3467097.



Additional Information

According to http://en.wikipedia.org/wiki/Bendamustine, bendamustine was first synthesized in 1963 by Ozegowski and Krebs in East Germany (the former German Democratic Republic). It is a white, water soluble microcrystalline powder with amphoteric properties. Until 1990 it was available only in East Germany. East German investigators found that it was useful for treating chronic lymphocytic leukemia, HodgkinÂ’s disease, non-HodgkinÂ’s lymphoma, multiple myeloma and lung cancer. Bendamustine received its first marketing approval in Germany, which is marketed under the tradename Ribomustin, by Astellas Pharma GmbH's licensee, Mundipharma International Corporation Limited, which it is indicated as a single-agent or in combination with other anti-cancer agents for indolent NHL, multiple myeloma, and CLL. SymBio Pharmaceuticals Ltd holds exclusive rights to develop and market bendamustine HCl in Japan and selected Asia Pacific Rim countries. In March 2008, Cephalon received approval from the United States Food and Drug Administration to market bendamustine in the US, where it is sold under the tradename Treanda, for treatment of CLL.  In October 2008, the FDA granted further approval to market Treanda for the treatment of indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.