Chlorambucil | CAS#305-03-3 | Alkylating Agent | Antineoplastic

MedKoo Cat#: 100150 | Name: Chlorambucil

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Chlorambucil is an orally-active antineoplastic aromatic nitrogen mustard. Chlorambucil alkylates and cross-links DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis.

Chemical Structure

Chlorambucil

CAS#305-03-3

Theoretical Analysis

MedKoo Cat#: 100150

Name: Chlorambucil

CAS#: 305-03-3

Chemical Formula: C14H19Cl2NO2

Exact Mass: 303.0793

Molecular Weight: 304.21

Elemental Analysis: C, 55.27; H, 6.30; Cl, 23.31; N, 4.60; O, 10.52

Price and Availability

Size	Price	Availability
100mg	USD 150.00	Ready to ship
200mg	USD 225.00	Ready to ship
500mg	USD 450.00	Ready to ship
1g	USD 650.00	Ready to ship
2g	USD 1,050.00	Ready to ship

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Synonym

chlorambucilum; chloraminophen; Chlorbutin; chlorbutine; chlorbutinum; chloroambucil; chlorobutin; chlorobutine; Leukersan; Leukoran; Lympholysin; phenylbutyric acid nitrogen mustard; US brand names: Ambochlorin; Amboclorin; Leukeran; Linfolizin. Foreign brand names: Altichlorambucil; Chloraminophene; Linfolysin. Abbreviations: CHL CLB; Code names: CB1348; WR139013.

IUPAC/Chemical Name

4-(4-(bis(2-chloroethyl)amino)phenyl)butanoic acid

InChi Key

JCKYGMPEJWAADB-UHFFFAOYSA-N

InChi Code

InChI=1S/C14H19Cl2NO2/c15-8-10-17(11-9-16)13-6-4-12(5-7-13)2-1-3-14(18)19/h4-7H,1-3,8-11H2,(H,18,19)

SMILES Code

O=C(O)CCCC1=CC=C(N(CCCl)CCCl)C=C1

Appearance

Pale brown to brown 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 in water

Shelf Life

>2 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

More Info

Chlorambucil (marketed as Leukeran by GlaxoSmithKline) is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia. It is a nitrogen mustard alkylating agent and can be given orally. In the past, chlorambucil has been used for treating some types of non-Hodgkin lymphoma, WaldenstrÃ¶m macroglobulinemia, polycythemia vera, trophoblastic neoplasms, and ovarian carcinoma. It also has been used as an immunosuppressive drug for various autoimmune and inflammatory conditions, such as nephrotic syndrome. Its current use is mainly in chronic lymphocytic leukemia, as it is well tolerated by most patients, though chlorambucil has been largely replaced by fludarabine as first-line treatment in younger patients. see http://en.wikipedia.org/wiki/Chlorambucil. LEUKERAN (chlorambucil) was first synthesized by Everett et al. It is a bifunctional alkylating agent of the nitrogen mustard type that has been found active against selected human neoplastic diseases. Chlorambucil is known chemically as 4-[bis(2-chlorethyl)amino]benzenebutanoic acid. Chlorambucil hydrolyzes in water and has a pKa of 5.8. LEUKERAN (chlorambucil) is available in tablet form for oral administration. Each film-coated tablet contains 2 mg chlorambucil and the inactive ingredients colloidal silicon dioxide, hypromellose, lactose (anhydrous), macrogol/PEG 400, microcrystalline cellulose, red iron oxide, stearic acid, titanium dioxide, and yellow iron oxide. CLINICAL PHARMACOLOGY Chlorambucil is rapidly and completely absorbed from the gastrointestinal tract. After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1 hour and the terminal elimination half-life (tÅ“) of the parent drug is estimated at 1.5 hours. Chlorambucil undergoes rapid metabolism to phenylacetic acid mustard, the major metabolite, and the combined chlorambucil and phenylacetic acid mustard urinary excretion is extremely low Â— less than 1% in 24 hours. In a study of 12 patients given single oral doses of 0.2 mg/kg of LEUKERAN, the mean dose (12 mg) adjusted (Â± SD) plasma chlorambucil Cmax was 492 Â± 160 ng/mL, the AUC was 883 Â± 329 ngÂ•h/mL, tÅ“ was 1.3 Â± 0.5 hours, and the W was 0.83 Â± 0.53 hours. For the major metabolite, phenylacetic acid mustard, the mean dose (12 mg) adjusted (Â± SD) plasma Cmax was 306 Â± 73 ng/mL, the AUC was 1204 Â± 285 ngÂ•h/mL, the t/ was 1.8 Â± 0.4 hours, and the tmax was 1.9 Â± 0.7 hours. Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels of chlorambucil have not been determined. Evidence of human teratogenicity suggests that the drug crosses the placenta. Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, which has antineoplastic activity. Chlorambucil and its major metabolite spontaneously degrade in vivo forming monohydroxy and dihydroxy derivatives. After a single dose of radiolabeled chlorambucil (14C), approximately 15% to 60% of the radioactivity appears in the urine after 24 hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard. In summary, the pharmacokinetic data suggest that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, lot#SGM50122

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Chlorambucil (CB-1348) is an alkylating agent.

In vitro activity:

Whether chlorambucil toxicity to BRCA2-deficient cells is due to ICL- (intra- and inter-strand crosslink -) inflicted DNA replication and DSB repair defects was assessed. The response of BRCA2-proficient and BRCA2-deficient DLD1 cells to chlorambucil was evaluated using time course experiments and immunoblotting for checkpoint activation markers (Fig 4A). RPA phosphorylation at Ser33, a marker for ATR activation and replication stress, was induced in BRCA2-proficient cells following exposure to 1 μM chlorambucil for 48 h. In contrast, BRCA2-deficient cells, with intrinsic defects in replication fork progression and stability, showed detectable levels of RPA Ser33 phosphorylation even in the absence of any treatment (0 h), and these were markedly increased upon incubation with 1 μM chlorambucil from 16 h onwards. BRCA2-deficient cells also showed elevated levels of KAP1 Ser824 phosphorylation, a signature of ATM-dependent checkpoint activation and DNA damage accumulation. Phosphorylated KAP1 was detected from 24 h of treatment with chlorambucil in BRCA2-deficient cells. As RPA phosphorylation occurs earlier (16 h), this suggests that replication stress may precede DSB formation in response to chlorambucil. Cleaved PARP, an apoptosis marker, was induced only in cells lacking BRCA2. PARP cleavage was detectable from 16 h onwards, similarly to Ser33 RPA phosphorylation, supporting the concept that replication stress underlies chlorambucil toxicity to BRCA2-deficient cells. Reference: EMBO Mol Med. 2019 Jul;11(7):e9982. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609913/

In vivo activity:

Chlorambucil had no effect on the growth of BRCA2-proficient tumours (Fig 5A), but it caused a striking reduction in BRCA2-deficient tumour growth (Fig 5B). When the drug was administered intraperitoneally at doses of 3 mg/kg daily for 10 days (with a 2-day break after day 5), tumour eradication was observed in all mice within 21 days from treatment initiation. The dose administed in mice was lowered and it was observed that BRCA2-deficient tumours were eliminated even at doses of 1 mg/kg daily chlorambucil. Reference: EMBO Mol Med. 2019 Jul;11(7):e9982. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609913/

	Solvent	mg/mL	mM
Solubility
	DMSO	42.0	138.06
	Ethanol	60.0	197.23

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 304.21 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.

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. Tacconi EM, Badie S, De Gregoriis G, Reisländer T, Lai X, Porru M, Folio C, Moore J, Kopp A, Baguña Torres J, Sneddon D, Green M, Dedic S, Lee JW, Batra AS, Rueda OM, Bruna A, Leonetti C, Caldas C, Cornelissen B, Brino L, Ryan A, Biroccio A, Tarsounas M. Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance. EMBO Mol Med. 2019 Jul;11(7):e9982. doi: 10.15252/emmm.201809982. Epub 2019 May 24. PMID: 31273933; PMCID: PMC6609913.

In vitro protocol:

In vivo protocol:

1: National Toxicology Program. Chlorambucil. Rep Carcinog. 2011;12:90-1. PMID: 21850122. 2: Giles FJ, Smith MP, Goldstone AH. Chlorambucil lung toxicity. Acta Haematol. 1990;83(3):156-8. doi: 10.1159/000205195. PMID: 2109457. 3: Li WX, Yan X, Shi CR, Zhang AP. Chlorambucil for patients with primary biliary cirrhosis. Cochrane Database Syst Rev. 2012 Sep 12;(9):CD008714. doi: 10.1002/14651858.CD008714.pub2. PMID: 22972125. 4: Chlorambucil. IARC Monogr Eval Carcinog Risk Chem Man. 1975;9:125-34. PMID: 791828. 5: Zucca E, Conconi A, Martinelli G, Bouabdallah R, Tucci A, Vitolo U, Martelli M, Pettengell R, Salles G, Sebban C, Guillermo AL, Pinotti G, Devizzi L, Morschhauser F, Tilly H, Torri V, Hohaus S, Ferreri AJM, Zachée P, Bosly A, Haioun C, Stelitano C, Bellei M, Ponzoni M, Moreau A, Jack A, Campo E, Mazzucchelli L, Cavalli F, Johnson P, Thieblemont C. Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy. J Clin Oncol. 2017 Jun 10;35(17):1905-1912. doi: 10.1200/JCO.2016.70.6994. Epub 2017 Mar 29. Erratum in: J Clin Oncol. 2017 Jul 10;35(20):2342. PMID: 28355112. 6: Birnbaum AD, Oh F, Sahin O, Little DM, Tessler HH, Goldstein DA. Chlorambucil and malignancy. Ophthalmology. 2010 Jul;117(7):1466-1466.e1. doi: 10.1016/j.ophtha.2010.03.023. PMID: 20610006. 7: Palmer RG, Denman AM. Malignancies induced by chlorambucil. Cancer Treat Rev. 1984 Jun;11(2):121-9. doi: 10.1016/0305-7372(84)90004-5. PMID: 6388834. 8: Begleiter A, Mowat M, Israels LG, Johnston JB. Chlorambucil in chronic lymphocytic leukemia: mechanism of action. Leuk Lymphoma. 1996 Oct;23(3-4):187-201. doi: 10.3109/10428199609054821. PMID: 9031099. 9: Shayegh A, Khalatbari F, Zonoubi N, Zarazvand F, Monavvari F, Hejazinia H, Ebrahimi SES, Hamedani MP, Ali V, Hadadian S, Farzaneh J, Seyedhamzeh M, Ardestani MS. Chlorambucil-Chitosan Nano-Conjugate: An Efficient Agent Against Breast Cancer Targeted Therapy. Curr Drug Deliv. 2021;18(6):721-728. doi: 10.2174/1567201817666201027122620. PMID: 33109048. 10: Chlorambucil. Rep Carcinog. 2004;11:III47-8. PMID: 21089821. 11: Chlorambucil. IARC Monogr Eval Carcinog Risk Chem Hum. 1981 May;26:115-36. PMID: 6944255. 12: Zhang L, Cheng Y, Liu YG, Chen X, Liu H. Anticancer Effect of Chlorambucil Enhanced by Chiral Phthalidyl Promoiety. Chem Biodivers. 2023 Jan;20(1):e202201025. doi: 10.1002/cbdv.202201025. Epub 2022 Dec 8. PMID: 36427041. 13: Carr ME Jr. Chlorambucil induced pulmonary fibrosis: report of a case and review. Va Med. 1986 Nov;113(11):677-80. PMID: 3538689. 14: Catovsky D, Else M, Richards S. Chlorambucil--still not bad: a reappraisal. Clin Lymphoma Myeloma Leuk. 2011 Jun;11 Suppl 1:S2-6. doi: 10.1016/j.clml.2011.02.006. Epub 2011 May 6. PMID: 22035743. 15: Huang P, Wang G, Wang Z, Zhang C, Wang F, Cui X, Guo S, Huang W, Zhang R, Yan D. Floxuridine-chlorambucil conjugate nanodrugs for ovarian cancer combination chemotherapy. Colloids Surf B Biointerfaces. 2020 Oct;194:111164. doi: 10.1016/j.colsurfb.2020.111164. Epub 2020 Jun 2. PMID: 32526636. 16: Cameron S. Chlorambucil and leukemia. N Engl J Med. 1977 May 5;296(18):1065. doi: 10.1056/nejm197705052961814. PMID: 846551. 17: Steinberg AD. Chlorambucil in the treatment of patients with immune-mediated rheumatic diseases. Arthritis Rheum. 1993 Mar;36(3):325-8. doi: 10.1002/art.1780360306. PMID: 8452576. 18: Green AA, Naiman JL. Chlorambucil poisoning. Am J Dis Child. 1968 Aug;116(2):190-1. doi: 10.1001/archpedi.1968.02100020192013. PMID: 5659298. 19: Zhang M, Jin X, Gao M, Zhang Y, Tang BZ. A Self-Reporting Fluorescent Salicylaldehyde-Chlorambucil Conjugate as a Type-II ICD Inducer for Cancer Vaccines. Adv Mater. 2022 Sep;34(36):e2205701. doi: 10.1002/adma.202205701. Epub 2022 Aug 8. PMID: 35863361. 20: McLean A, Newell D, Baker G, Connors T. The metabolism of chlorambucil. Biochem Pharmacol. 1980 Jul 15;29(14):2039-47. doi: 10.1016/0006-2952(80)90489-x. PMID: 7406916.

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Description:

Chemical Structure

Theoretical Analysis

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Preparing Stock Solutions

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