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Identification
NameMelphalan
Accession NumberDB01042  (APRD00118)
TypeSmall Molecule
GroupsApproved
Description

An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer – melphalan, the racemic mixture – merphalan, and the dextro isomer – medphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. [PubChem]

Structure
Thumb
Synonyms
3-(P-(Bis(2-chloroethyl)amino)phenyl)-L-alanine
3-P-(Di(2-chloroethyl)amino)-phenyl-L-alanine
4-(Bis(2-chloroethyl)amino)-L-phenylalanine
L-3-(P-(Bis(2-chloroethyl)amino)phenyl)alanine
L-PAM
L-Phenylalanine mustard
L-Sarcolysine
Melfalano
Melphalanum
p-Bis(beta-chloroethyl)aminophenylalanine
P-Di-(2-chloroethyl)amino-L-phenylalanine
P-L-Sarcolysin
P-N-Bis(2-chloroethyl)amino-L-phenylalanine
p-N,N-bis(2-chloroethyl)amino-L-phenylalanine
Phenylalanine mustard
Phenylalanine nitrogen mustard
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Alkerantablet, film coated2 mg/1oralApo Pharma Usa, Inc2011-01-01Not applicableUs
Alkerantablet2 mgoralAspen Pharma Trading Limited1964-12-31Not applicableCanada
AlkerankitApo Pharma Usa, Inc2011-01-01Not applicableUs
Evomelainjection, powder, lyophilized, for solution50 mg/10mLintravenousSpectrum Pharmaceuticals, Inc.2016-03-31Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Melphalan HydrochloridekitGenera Medix Inc.2009-10-27Not applicableUs
Melphalan HydrochloridekitMylan Institutional LLC2014-09-29Not applicableUs
Melphalan HydrochloridekitMylan Institutional LLC2013-01-10Not applicableUs
Melphalan HydrochloridekitMylan Institutional LLC2013-01-10Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Melphalan hydrochloride
ThumbNot applicableDBSALT001019
Categories
UNIIQ41OR9510P
CAS number148-82-3
WeightAverage: 305.2
Monoisotopic: 304.074533244
Chemical FormulaC13H18Cl2N2O2
InChI KeyInChIKey=SGDBTWWWUNNDEQ-LBPRGKRZSA-N
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
IUPAC Name
(2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid
SMILES
N[C@@H](CC1=CC=C(C=C1)N(CCCl)CCCl)C(O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylpropanoic acids. These are compounds with a structure containing a benzene ring conjugated to a propanoic acid.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassPhenylpropanoic acids
Sub ClassNot Available
Direct ParentPhenylpropanoic acids
Alternative Parents
Substituents
  • 3-phenylpropanoic-acid
  • L-alpha-amino acid
  • Amphetamine or derivatives
  • Alpha-amino acid or derivatives
  • Alpha-amino acid
  • Substituted aniline
  • Dialkylarylamine
  • Nitrogen mustard
  • Aralkylamine
  • Aniline
  • Amino fatty acid
  • Fatty acyl
  • Benzenoid
  • Monocyclic benzene moiety
  • Tertiary amine
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Primary aliphatic amine
  • Carbonyl group
  • Amine
  • Alkyl halide
  • Alkyl chloride
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Has also been used alone or as part of various chemotherapeutic regimens as an adjunct to surgery in the treatment of breast cancer, alone or in combination regimens for palliative treatment of locally recurrent or unresectable in-transit metastatic melanoma of the extremities, as well as for the treatment of amyloidosis with prednisone.
PharmacodynamicsMelphalan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.
Mechanism of actionAlkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases (primarily at the N-7 position of guanine and to a lesser extent, at the N-3 position of adenine), forming monoadducts and resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.
Related Articles
AbsorptionIncomplete, variable, 25-89% post oral dose
Volume of distribution
  • 0.5 L/kg
Protein bindingModerate to high (60 to 90%), primarily to albumin and, to a lesser extent, alpha 1-acid glycoprotein. 30% is irreversibly bound.
Metabolism

Melphalan is not actively metabolised, it spontaneously degrades to mono and dihydroxy products.

Route of eliminationThe 24-hour urinary excretion of parent drug in these patients was 10% ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug.
Half life1.5 (±0.83) hours
ClearanceNot Available
ToxicityVomiting, ulceration of the mouth, diarrhea, and hemorrhage of the gastrointestinal tract; The principal toxic effect is bone marrow suppression. LD50=11.2 mg/kg (orally in rat)
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9523
Blood Brain Barrier-0.6073
Caco-2 permeable+0.5
P-glycoprotein substrateSubstrate0.5
P-glycoprotein inhibitor INon-inhibitor0.983
P-glycoprotein inhibitor IINon-inhibitor0.9192
Renal organic cation transporterNon-inhibitor0.811
CYP450 2C9 substrateNon-substrate0.8457
CYP450 2D6 substrateNon-substrate0.7432
CYP450 3A4 substrateNon-substrate0.7553
CYP450 1A2 substrateInhibitor0.779
CYP450 2C9 inhibitorNon-inhibitor0.9348
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9193
CYP450 3A4 inhibitorInhibitor0.7959
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9863
Ames testAMES toxic0.9108
CarcinogenicityNon-carcinogens0.7873
BiodegradationNot ready biodegradable0.9746
Rat acute toxicity3.9179 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8187
hERG inhibition (predictor II)Non-inhibitor0.8488
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Tabletoral2 mg
Tablet, film coatedoral2 mg/1
Injection, powder, lyophilized, for solutionintravenous50 mg/10mL
Kit
Prices
Unit descriptionCostUnit
Alkeran 50 mg vial1971.72USD vial
Melphalan hcl 50 mg vial1845.6USD vial
Alkeran 2 mg tablet5.65USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA1341114 No2000-10-102017-10-10Canada
US8410077 No2009-03-132029-03-13Us
US9200088 No2009-03-132029-03-13Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point182.5 °CPhysProp
water solubility< 0.1 g/100 mL at 22 °CNot Available
logP-0.52SANGSTER,J (1994) @pH=7.4
Predicted Properties
PropertyValueSource
Water Solubility0.358 mg/mLALOGPS
logP-0.22ALOGPS
logP0.25ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)1.29ChemAxon
pKa (Strongest Basic)9.51ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area66.56 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity78.23 m3·mol-1ChemAxon
Polarizability31.38 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US3032584
General References
  1. Loeber R, Michaelson E, Fang Q, Campbell C, Pegg AE, Tretyakova N: Cross-linking of the DNA repair protein Omicron6-alkylguanine DNA alkyltransferase to DNA in the presence of antitumor nitrogen mustards. Chem Res Toxicol. 2008 Apr;21(4):787-95. doi: 10.1021/tx7004508. Epub 2008 Feb 14. [PubMed:18324787 ]
  2. Souliotis VL, Dimopoulos MA, Episkopou HG, Kyrtopoulos SA, Sfikakis PP: Preferential in vivo DNA repair of melphalan-induced damage in human genes is greatly affected by the local chromatin structure. DNA Repair (Amst). 2006 Aug 13;5(8):972-85. Epub 2006 Jun 15. [PubMed:16781199 ]
  3. Moscow JA, Swanson CA, Cowan KH: Decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan. Br J Cancer. 1993 Oct;68(4):732-7. [PubMed:8398701 ]
External Links
ATC CodesL01AA03
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelDownload (175 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
CarmustineThe risk or severity of adverse effects can be increased when Melphalan is combined with Carmustine.
ClozapineThe risk or severity of adverse effects can be increased when Melphalan is combined with Clozapine.
CyclosporineMelphalan may increase the nephrotoxic activities of Cyclosporine.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Melphalan.
LeflunomideThe risk or severity of adverse effects can be increased when Melphalan is combined with Leflunomide.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Melphalan.
Nalidixic AcidThe risk or severity of adverse effects can be increased when Nalidixic Acid is combined with Melphalan.
NatalizumabThe risk or severity of adverse effects can be increased when Melphalan is combined with Natalizumab.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Melphalan.
RoflumilastRoflumilast may increase the immunosuppressive activities of Melphalan.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Melphalan.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Melphalan.
TofacitinibMelphalan may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Melphalan.
Food Interactions
  • Take on an empty stomach. Food decreases bioavailabilty by approximately 30%. Increase liquid intake.

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
cross-linking/alkylation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
  3. Monahan SD, Subbotin VM, Budker VG, Slattum PM, Neal ZC, Herweijer H, Wolff JA: Rapidly reversible hydrophobization: an approach to high first-pass drug extraction. Chem Biol. 2007 Sep;14(9):1065-77. [PubMed:17884638 ]
  4. Lee PC, Kakadiya R, Su TL, Lee TC: Combination of bifunctional alkylating agent and arsenic trioxide synergistically suppresses the growth of drug-resistant tumor cells. Neoplasia. 2010 May;12(5):376-87. [PubMed:20454509 ]
  5. Wang F, Li F, Ganguly M, Marky LA, Gold B, Egli M, Stone MP: A bridging water anchors the tethered 5-(3-aminopropyl)-2'-deoxyuridine amine in the DNA major groove proximate to the N+2 C.G base pair: implications for formation of interstrand 5'-GNC-3' cross-links by nitrogen mustards. Biochemistry. 2008 Jul 8;47(27):7147-57. doi: 10.1021/bi800375m. Epub 2008 Jun 13. [PubMed:18549246 ]
  6. Vasquez KM: Targeting and processing of site-specific DNA interstrand crosslinks. Environ Mol Mutagen. 2010 Jul;51(6):527-39. doi: 10.1002/em.20557. [PubMed:20196133 ]
  7. Dimopoulos MA, Souliotis VL, Anagnostopoulos A, Bamia C, Pouli A, Baltadakis I, Terpos E, Kyrtopoulos SA, Sfikakis PP: Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma. Haematologica. 2007 Nov;92(11):1505-12. [PubMed:18024399 ]
  8. Chen Q, Van der Sluis PC, Boulware D, Hazlehurst LA, Dalton WS: The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells. Blood. 2005 Jul 15;106(2):698-705. Epub 2005 Mar 31. [PubMed:15802532 ]
  9. Souliotis VL, Dimopoulos MA, Episkopou HG, Kyrtopoulos SA, Sfikakis PP: Preferential in vivo DNA repair of melphalan-induced damage in human genes is greatly affected by the local chromatin structure. DNA Repair (Amst). 2006 Aug 13;5(8):972-85. Epub 2006 Jun 15. [PubMed:16781199 ]
  10. Loeber R, Michaelson E, Fang Q, Campbell C, Pegg AE, Tretyakova N: Cross-linking of the DNA repair protein Omicron6-alkylguanine DNA alkyltransferase to DNA in the presence of antitumor nitrogen mustards. Chem Res Toxicol. 2008 Apr;21(4):787-95. doi: 10.1021/tx7004508. Epub 2008 Feb 14. [PubMed:18324787 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Toxin transporter activity
Specific Function:
Mediates potential-dependent transport of a variety of organic cations. May play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.
Gene Name:
SLC22A3
Uniprot ID:
O75751
Molecular Weight:
61279.485 Da
References
  1. Shnitsar V, Eckardt R, Gupta S, Grottker J, Muller GA, Koepsell H, Burckhardt G, Hagos Y: Expression of human organic cation transporter 3 in kidney carcinoma cell lines increases chemosensitivity to melphalan, irinotecan, and vincristine. Cancer Res. 2009 Feb 15;69(4):1494-501. doi: 10.1158/0008-5472.CAN-08-2483. Epub 2009 Feb 3. [PubMed:19190342 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Peptide antigen binding
Specific Function:
Sodium-independent, high-affinity transport of large neutral amino acids such as phenylalanine, tyrosine, leucine, arginine and tryptophan, when associated with SLC3A2/4F2hc. Involved in cellular amino acid uptake. Acts as an amino acid exchanger. Involved in the transport of L-DOPA across the blood-brain barrier, and that of thyroid hormones triiodothyronine (T3) and thyroxine (T4) across the ...
Gene Name:
SLC7A5
Uniprot ID:
Q01650
Molecular Weight:
55009.62 Da
References
  1. Moscow JA, Swanson CA, Cowan KH: Decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan. Br J Cancer. 1993 Oct;68(4):732-7. [PubMed:8398701 ]
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Drug created on June 13, 2005 07:24 / Updated on June 26, 2016 02:27