Melphalan (T3D4702)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (1)XML
Targets (1)
Record Information
Version2.0
Creation Date2014-09-11 02:05:38 UTC
Update Date2014-12-24 20:26:55 UTC
Accession NumberT3D4702
Identification
Common NameMelphalan
ClassSmall Molecule
DescriptionAn 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.
Compound Type
  • Amine
  • Drug
  • Metabolite
  • Organic Compound
  • Organochloride
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
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
Alkeran
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,N-bis(2-chloroethyl)amino-L-phenylalanine
P-N-Bis(2-chloroethyl)amino-L-phenylalanine
Phenylalanine mustard
Phenylalanine nitrogen mustard
Chemical FormulaC13H18Cl2N2O2
Average Molecular Mass305.200 g/mol
Monoisotopic Mass304.075 g/mol
CAS Registry Number148-82-3
IUPAC Name(2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid
Traditional Namemelphalan
SMILES[H][C@](N)(CC1=CC=C(C=C1)N(CCCl)CCCl)C(O)=O
InChI IdentifierInChI=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
InChI KeyInChIKey=SGDBTWWWUNNDEQ-LBPRGKRZSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenylalanine and derivatives. Phenylalanine and derivatives are compounds containing phenylalanine or a derivative thereof resulting from reaction of phenylalanine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentPhenylalanine and derivatives
Alternative Parents
Substituents
  • Phenylalanine or derivatives
  • 3-phenylpropanoic-acid
  • Alpha-amino acid
  • Amphetamine or derivatives
  • L-alpha-amino acid
  • Nitrogen mustard
  • Tertiary aliphatic/aromatic amine
  • Aniline or substituted anilines
  • Dialkylarylamine
  • Aralkylamine
  • Monocyclic benzene moiety
  • Benzenoid
  • Amino acid
  • Tertiary amine
  • Carboxylic acid
  • Monocarboxylic acid or derivatives
  • Organic oxide
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Hydrocarbon derivative
  • Organic nitrogen compound
  • Primary aliphatic amine
  • Primary amine
  • Carbonyl group
  • Organopnictogen compound
  • Alkyl halide
  • Amine
  • Organic oxygen compound
  • Alkyl chloride
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point182.5°C
Boiling PointNot Available
Solubility< 0.1 g/100 mL at 22°C
LogP-0.52
Predicted Properties
PropertyValueSource
Water Solubility0.36 g/LALOGPS
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 ŲChemAxon
Rotatable Bond Count8ChemAxon
Refractivity78.23 m³·mol⁻¹ChemAxon
Polarizability31.38 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-052f-3890000000-153ff87813e7a797c73b2017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-01c3-8295000000-421b0e52574345db725f2017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-000w-2930000000-b95beb5e9c3e61b7687f2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-000w-2930000000-b95beb5e9c3e61b7687f2017-09-14View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-0093000000-78045bae5e6c1e79e22d2016-08-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a4i-1490000000-3b1f7009692b1139989b2016-08-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-02t9-3930000000-b0f45ffda87388d4384a2016-08-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0udi-0049000000-8c401366ace5d7fc1f082016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0v4i-1192000000-fd136d877921c8afed952016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00di-9530000000-511158435cb1ef0630852016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-0095000000-3f3242a1d9debe0c83152021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00bi-0090000000-91067233804f48cd760a2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014j-0930000000-af3e37be6b85ec7f144b2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-7090000000-6793f4f7ed0a2c22f9722021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-9000000000-c2fa753da65a4bac80a12021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-001i-9000000000-ed9c052b92676bc8a30b2021-10-11View Spectrum
1D NMR13C NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
Toxicity Profile
Route of ExposureIncomplete, variable, 25-89% post oral dose
Mechanism of ToxicityAlkylating 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.
MetabolismMelphalan is not actively metabolised, it spontaneously degrades to mono and dihydroxy products. Route of Elimination: The 24-hour urinary excretion of parent drug in these patients was 10% Њ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug. Half Life: 1.5 (±0.83) hours
Toxicity ValuesLD50=11.2 mg/kg (orally in rat)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)1, carcinogenic to humans. (4)
Uses/SourcesFor 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.
Minimum Risk LevelNot Available
Health EffectsThe principal toxic effect is bone marrow suppression.
SymptomsVomiting, ulceration of the mouth, diarrhea, and hemorrhage of the gastrointestinal tract.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01042
HMDB IDHMDB15176
PubChem Compound ID460612
ChEMBL IDCHEMBL852
ChemSpider ID405297
KEGG IDC07122
UniProt IDNot Available
OMIM ID
ChEBI ID28876
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkMelphalan
References
Synthesis Reference

DrugSyn.org

MSDST3D4702.pdf
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. [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. [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. [8398701 ]
  4. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

1. DNA
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. [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. [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. [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. [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. [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. [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. [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. [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. [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. [18324787 ]