Melphalan

Melphalan, sold under the brand name Alkeran among others, is a chemotherapy medication used to treat multiple myeloma, ovarian cancer, melanoma, and AL amyloidosis.[4] It is taken by mouth or by injection into a vein.[4]

Melphalan
Clinical data
Trade namesAlkeran, Evomela, Phelinun, others
Other names(2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid
AHFS/Drugs.comMonograph
MedlinePlusa682220
License data
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability25–89% (By mouth)
MetabolismHydrolysis to inactive metabolites
Elimination half-life1.5 ± 0.8 hours
ExcretionKidney (IV: 5.8–21.3%)
Identifiers
IUPAC name
  • 4-[bis(2-Chloroethyl)amino]-L-phenylalanine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.207
Chemical and physical data
FormulaC13H18Cl2N2O2
Molar mass305.20 g·mol−1
3D model (JSmol)
SMILES
  • c1cc(ccc1C[C@@H](C(=O)O)N)N(CCCl)CCCl
InChI
  • InChI=1S/C13H18Cl2N2O2/c14-5-7-17(8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19/h1-4,12H,5-9,16H2,(H,18,19)/t12-/m0/s1 Y
  • Key:SGDBTWWWUNNDEQ-LBPRGKRZSA-N Y
  (verify)

Common side effects include nausea and bone marrow suppression.[4] Other severe side effects may include anaphylaxis and the development of other cancers.[4] Use during pregnancy may result in harm to the fetus.[5] Melphalan belongs to the class of nitrogen mustard alkylating agents.[4] It works by interfering with the creation of DNA and RNA.[4]

Melphalan was approved for medical use in the United States in 1964.[4] It is on the World Health Organization's List of Essential Medicines.[6] It is available as a generic medication.[7]

Medical uses

It is used to treat multiple myeloma,[8] ovarian cancer, AL amyloidosis, and occasionally malignant melanoma.

The agent was first investigated as a possible drug for use in melanoma, it was not found to be effective.

In 2016, it was approved in the U.S. for:

Melphalan is used to treat ocular retinoblastoma, a pediatric solid tumor. This is accomplished via transarterial catheter based slow pulsed infusion into the ophthalmic artery.[9]

Side effects

Common side effects include:[4]

Less common side effects include:

Mechanism of action

Melphalan chemically alters the DNA nucleotide guanine through alkylation, and causes linkages between strands of DNA. This chemical alteration inhibits DNA synthesis and RNA synthesis, functions necessary for cells to survive. These changes cause cytotoxicity in both dividing and non-dividing tumor cells.[10] Tumor cells spend less time in resting phases than normal cells so at any given time, they are more likely to be metabolically active than most normal host cells. The rationale behind incorporating an alkylating function in a molecule resembling a primary cellular metabolite was to get a greater safety margin by fooling tumor cells into taking up the toxin preferentially.

Synthesis
Syntheses:[11][12][13] U.S. Patent 3,032,584; U.S. Patent 3,032,585 (both 1962 to NRDC).

4-Nitro-L-phenylalanine (1) was converted to its phthalimide by heating with phthalic anhydride, and this was converted to its ethyl ester (2). Catalytic hydrogenation produced the corresponding aniline. Heating in acid with oxirane, followed by treatment with phosphorus oxychloride provided the bischloride, and removal of the protecting groups by heating in hydrochloric acid gave melphalan (3).

Society and culture

On 17 September 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for melphalan.[14] The applicant for this medicinal product is ADIENNE S.r.l. S.U.[14] Melphalan was approved for medical use in the European Union in November 2020.[3]

References
  1. "Alkeran- melphalan tablet, film coated". DailyMed. 18 November 2019. Retrieved 23 April 2022.
  2. "Evomela- melphalan injection, powder, lyophilized, for solution". DailyMed. 31 December 2021. Retrieved 23 April 2022.
  3. "Phelinun EPAR". European Medicines Agency (EMA). 15 September 2020. Retrieved 23 April 2022. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. "Melphalan Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 9 October 2019.
  5. "Melphalan Use During Pregnancy". Drugs.com. Retrieved 9 October 2019.
  6. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 873–874. ISBN 9780857113382.
  8. Facon T, Mary JY, Hulin C, et al. (October 2007). "Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial". Lancet. 370 (9594): 1209–18. doi:10.1016/S0140-6736(07)61537-2. PMID 17920916. S2CID 10450108.
  9. Gobin YP, Dunkel IJ, Marr BP, et al. (June 2011). "Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience". Arch Ophthalmol. 129 (6): 732–7. doi:10.1001/archophthalmol.2011.5. PMID 21320950.
  10. "Melphalan". National Cancer Institute. Retrieved 4 August 2014.
  11. Bergel F, Stock JA (1954). "Cyto-active amino-acid and peptide derivatives. Part I. Substituted phenylalanines". Journal of the Chemical Society (Resumed): 2409. doi:10.1039/JR9540002409.
  12. Bergel F, Burnop VC, Stock JA (1955). "Cyto-active amino-acids and peptides. Part II. Resolution of para-substituted phenylalanines and synthesis of p-di-(2-chloroethyl)amino-DL-phenyl[?-14C]alanine". Journal of the Chemical Society (Resumed): 1223–1230. doi:10.1039/JR9550001223.
  13. Larionov LF, Khokhlov AS, Shkodinskaja EN, Vasina OS, Troosheikina VI, Novikova MA (1955). "Studies on the anti-tumour activity of p-di-(2-chloroethyl) aminophenylalanine (sarcolysine)". Lancet. 266 (6882): 169–71. doi:10.1016/S0140-6736(55)92736-7. PMID 13243678.
  14. "Phelinun: Pending EC decision". European Medicines Agency (EMA). 18 September 2020. Retrieved 21 September 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  • "Melphalan". Drug Information Portal. U.S. National Library of Medicine.
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