Melphalan

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Melphalan
Melphalan.svg
Melphalan ball-and-stick.png
Clinical data
Trade names Alkeran
AHFS/Drugs.com Monograph
MedlinePlus a682220
Routes of
administration
Oral (tablets), intravenous
ATC code L01AA03 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 25–89% (oral)
Metabolism Hydrolysis to inactive metabolites
Biological half-life 1.5 ± 0.8 hours
Excretion Renal (IV: 5.8–21.3%)
Identifiers
Synonyms (2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid
CAS Number 148-82-3 YesY
PubChem (CID) 460612
IUPHAR/BPS 7620
DrugBank DB01042 YesY
ChemSpider 405297 YesY
UNII Q41OR9510P YesY
KEGG D00369 YesY
ChEBI CHEBI:28876 YesY
ChEMBL CHEMBL852 YesY
ECHA InfoCard 100.005.207
Chemical and physical data
Formula C13H18Cl2N2O2
Molar mass 305.2 g/mol
3D model (Jmol) Interactive image
  (verify)

Melphalan (trade name Alkeran, in former USSR also known as Sarcolysin) is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.

An alkylating agent adds an alkyl group (CnH2n+1) to DNA. It attaches the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring.

Otherwise known as L-phenylalanine mustard, or L-PAM, melphalan is a phenylalanine derivative of mechlorethamine.

Mechanism of action[edit]

Melphalan chemically alters through alkylation of the DNA nucleotide guanine, 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.[1]

Uses[edit]

It is used to treat multiple myeloma,[2] 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.

On March 15, 2016 it was approved by the U.S. FDA under the trade name Evomela for:

Melphalan is currently being used to treat ocular retinoblastoma, a pediatric solid tumor. This is accomplished via transarterial catheter based slow pulsed infusion into the ophthalmic artery.[4]

Administration[edit]

Oral or intravenous; dosing varies by purpose and route of administration as well as patient weight.

Melphalan Prescribing Information: Alkeran[5]

Melphalan Patient Information: MedlinePlus[6]

Melphalan Material Safety Data Sheet (MSDS): Sequoia Research Products[7]

Side effects[edit]

Common side effects include:

Less common side effects include:

Synthesis[edit]

Another amino acid-like drug is the antineoplastic agent melphalan. 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.

p-Nitrophenyl-alanine (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).

References[edit]

  1. ^ "Melphalan". National Cancer Institute. Retrieved 4 August 2014. 
  2. ^ 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. 
  3. ^ "Evomela (melphalan) for Injection, for Intravenous Use. Full Prescribing Information". Spectrum Pharmaceuticals, Inc. Irvine, CA 92618. Retrieved 17 March 2016. 
  4. ^ Gobin YP, Dunkel IJ, Marr BP, et al. (Jun 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. 
  5. ^ celgene.com
  6. ^ nlm.nih.gov
  7. ^ seqchem.com
  8. ^ Bergel, F.; Stock, J. A. (1954). "Cyto-active amino-acid and peptide derivatives. Part I. Substituted phenylalanines". Journal of the Chemical Society (Resumed): 2409. doi:10.1039/JR9540002409. 
  9. ^ Bergel, F.; Burnop, V. C. E.; Stock, J. A. (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. doi:10.1039/JR9550001223. 
  10. ^ Larionov, L.F.; Khokhlov, A.S.; Shkodinskaja, E.N.; Vasina, O.S.; Troosheikina, V.I.; Novikova, M.A. (1955). "STUDIES ON THE ANTI-TUMOUR ACTIVITY OF p-DI-(2-CHLOROETHYL) AMINOPHENYLALANINE (SARCOLYSINE)". The Lancet. 266 (6882): 169. doi:10.1016/S0140-6736(55)92736-7.