MELPHALAN HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C13H18Cl2N2O2.ClH
Molecular Weight	341.661
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.N[C@@H](CC1=CC=C(C=C1)N(CCCl)CCCl)C(O)=O

InChI

InChIKey=OUUYBRCCFUEMLH-YDALLXLXSA-N

InChI=1S/C13H18Cl2N2O2.ClH/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);1H/t12-;/m0./s1

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C13H18Cl2N2O2
Molecular Weight	305.2
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23584492 | https://www.ncbi.nlm.nih.gov/pubmed/29029544 | https://www.oncopeptides.se/en/about-ygalo/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf
Curator's Comment: description was created based on several sources, including,http://www.nhs.uk/ipgmedia/National/Macmillan%20Cancer%20Support/assets/MelphalanMCS5pages.pdf http://www.bloodjournal.org/content/bloodjournal/100/1/224.full.pdf

Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent which produces a number of DNA adducts with the DNA interstrand crosslink (ICL) considered to be the critical cytotoxic lesion. Melphalan is used to treat different cancers including myeloma, melanoma and ovarian cancer.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 278 Target ID: CHEMBL2311221 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf	Crosslinking Agent 81

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple myeloma 159 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf	Palliative		Approved 8429	ALKERAN Approved Use ALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Launch Date 1964
Epithelial carcinoma of the ovary 4 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf	Palliative		Approved 8429	ALKERAN Approved Use ALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Launch Date 1964

C_max

Value	Dose	Co-administered	Analyte	Population
212 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf	0.25 mg/kg single, oral dose: 0.25 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		MELPHALAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
12.84 mg × h/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26879446	200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:		MELPHALAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
498 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf	0.25 mg/kg single, oral dose: 0.25 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		MELPHALAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
1 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf	0.25 mg/kg single, oral dose: 0.25 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		MELPHALAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
70% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf			MELPHALAN plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
40 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 40 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 40 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	unhealthy, 18–74 n = 7 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	DLT: Thrombocytopenia, Neutropenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 57%) Neutropenia (grade 4, 57%) Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60
30 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 30 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 30 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	unhealthy, 18–74 n = 9 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	DLT: Thrombocytopenia, Neutropenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 44%) Neutropenia (grade 4, 44%) Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60
200 mg/m2 1 times / 70 days multiple, intravenous MTD Dose: 200 mg/m2, 1 times / 70 days Route: intravenous Route: multiple Dose: 200 mg/m2, 1 times / 70 days Sources: https://pubmed.ncbi.nlm.nih.gov/9720737 Page: p.248, 250	unhealthy, 33–65 n = 55 Health Status: unhealthy Condition: Multiple myeloma Age Group: 33–65 Sex: M+F Population Size: 55 Sources: https://pubmed.ncbi.nlm.nih.gov/9720737 Page: p.248, 250	Disc. AE: Toxic reaction (NOS), Bacterial infection... AEs leading to discontinuation/dose reduction: Toxic reaction (NOS) (grade 4, 1.8%) Bacterial infection (grade 5, 3.6%) Systemic herpes zoster infection (grade 5, 1.8%) Sources: https://pubmed.ncbi.nlm.nih.gov/9720737 Page: p.248, 250
100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf Page: p.1	Disc. AE: Bone marrow depression, Hypersensitivity reaction... AEs leading to discontinuation/dose reduction: Bone marrow depression (severe) Hypersensitivity reaction (2%) Anaphylaxis Gastrointestinal toxicity Nausea Vomiting Diarrhea Mucositis oral Fetal damage Infertility Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf Page: p.1

AEs

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:28876	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:28876
ChemicalBook	CB2492687	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2492687
MolPort	MolPort-003-665-535	https://www.molport.com/shop/molecule-link/MolPort-003-665-535
ZINC	ZINC000000001673	http://zinc15.docking.org/substances/ZINC000000001673
eMolecules	525665	https://www.emolecules.com/cgi-bin/more?vid=525665

PubMed

Title	Date	PubMed
Prolonged apnea after succinylcholine in a case treated with cytostatics for cancer.	1972 Sep-Oct	4672170
[Diagnosis and treatment of plasma cell leukemia].	1973 Apr 27	4571885
Carcinoma of the breast. Occurence after treatment with melphalan for multiple myeloma.	1976 Oct 4	183029
[Refractory anemia with partial myeloblastosis in multiple myeloma treated with melphalan].	1977 Apr 9-16	194338
Cytomegalovirus pneumonia after treatment with melphalan and prednisone. Report of a case.	1978	206105
Drug testing using a soft agar stem cell assay on patient and xenograft tumor material.	1984 Sep	6207157
Melphalan-resistant multiple myeloma: results of treatment according to the M-2 protocol.	1985	3838922
Syndrome of inappropriate antidiuretic hormone secretion. A complication of high-dose intravenous melphalan.	1985 Jan 1	3965085
Altered pharmacokinetics in the mechanism of chemosensitization: effects of nitroimidazoles and other chemical modifiers on the pharmacokinetics, antitumour activity and acute toxicity of selected nitrogen mustards.	1986	3698174
L-phenylalanine mustard-dianhydrogalactitol and hyponatremia.	1986	3153241
Interferon alfa-2b/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial.	1987	3597002
Successful treatment of peripheral neuropathy with chemotherapy in osteosclerotic myeloma.	1987 May	3039073
[A case report of acute renal failure induced by melphalan in a patient with ovarian cancer].	1988 Nov	2849690
Interaction of melphalan and dexamethasone in a human myeloma cell line.	1991 Dec	1806033
Cyclophosphamide-associated carcinoma of urothelium: modalities for prevention.	1991 Nov	1949449
Melphalan antitumor efficacy and hepatotoxicity: the effect of variable infusion duration in the hepatic artery.	2003 Jun	12606622
In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa).	2003 Nov	14595385
Metaiodobenzylguanidine and hyperglycemia augment tumor response to isolated limb perfusion in a rodent model of human melanoma.	2004 Mar	14993021
Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan.	2005	15779864
Perspectives for combination therapy to overcome drug-resistant multiple myeloma.	2005 Aug	16019253
The nitrogen mustard melphalan activates mitogen-activated phosphorylated kinases (MAPK), nuclear factor-kappaB and inflammatory response in lung epithelial cells.	2005 Jul-Aug	16025434
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
The immunogenicity of dendritic cell-based vaccines is not hampered by doxorubicin and melphalan administration.	2005 Mar 15	15749863
In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor.	2005 Oct 15	16243825
The effect of intracellular ascorbate on the susceptibility of HL60 and Jurkat cells to chemotherapy agents.	2006 Oct	16951922
Hypercalcemia induced by 13 cis-retinoic acid in patients with neuroblastoma.	2008 Apr	18353067
Pharmacologic profiling of human and rat cytochrome P450 1A1 and 1A2 induction and competition.	2008 Dec	18493746
Cytogenetically defined myelodysplasia after melphalan-based autotransplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: the Arkansas experience in more than 3,000 patients treated since 1989.	2008 Jan 1	17895401
Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma.	2008 May	18388930
Cardiac toxicity of high-dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation.	2008 Sep	18548196
Multiple myeloma with a variant Burkitt-type translocation, t(2;8)(p12;q24), associated with hyperammonemia.	2009	19602793
Common peroneal nerve palsy following TNF-based isolated limb perfusion for irresectable extremity desmoid tumor.	2009 Dec	19944662
Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma.	2009 Dec 15	19934314
Development of rapid light-chain deposition disease in hepatic arteries with severe ischemic cholangitis in a multiple myeloma patient treated with melphalan, prednisone and lenalidomide.	2009 Jan	19101782
Cutaneous involvement in multiple myeloma and bortezomib.	2009 Nov	19259673
Excessive toxicity of once daily i.v. BU, melphalan and thiotepa followed by auto SCT on patients with non-Hodgkin's lymphoma.	2010 Apr	19767780
Efficacy and safety of once-weekly bortezomib in multiple myeloma patients.	2010 Dec 2	20807892
Thalidomide-induced phrenic nerve paralysis.	2010 Feb	20038224
Glutathione S-transferase M1 inhibits dexamethasone-induced apoptosis in association with the suppression of Bim through dual mechanisms in a lymphoblastic leukemia cell line.	2010 Mar	20067466
Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial.	2010 Nov	20864405
Inhalation of alkylating mustard causes long-term T cell-dependent inflammation in airways and growth of connective tissue.	2011 Feb 27	21129433
Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study.	2011 Jan	20874823
Bone marrow osteoblast damage by chemotherapeutic agents.	2012	22363485
In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells.	2013 Jun 1	23584492
The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo.	2013 Oct 1	23933387
FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1.	2013 Sep 5	23769903
In vitro and in vivo activity of melflufen (J1)in lymphoma.	2016 Apr 4	27044263
A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells.	2016 Aug	27098276
In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia.	2017 Jan 24	27974676
Melflufen - a peptidase-potentiated alkylating agent in clinical trials.	2017 Sep 12	29029544

Patents

Sample Use Guides

In Vivo Use Guide

Phase 3 clinical study (OCEAN, OP-103). Melflufen 40 mg i.v. on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.

Route of Administration: Intravenous

In Vitro Use Guide

Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:15:16 GMT 2023` Edited by `admin` on `Fri Dec 15 15:15:16 GMT 2023`
Record UNII	1VXP4V453T
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

MELPHALAN HYDROCHLORIDE

Common Name

English

CB-3025 HYDROCHLORIDE

Code

English

SARCOLYSIN HYDROCHLORIDE, L-

Common Name

English

MELPHALAN HYDROCHLORIDE [USP-RS]

Common Name

English

MELPHALAN HYDROCHLORIDE [VANDF]

Common Name

English

L-PHENYLALANINE, 4-(BIS(2-CHLOROETHYL)AMINO)-, HYDROCHLORIDE (1:1)

Systematic Name

English

EVOMELA

Brand Name

English

CB 3025 HYDROCHLORIDE

Code

English

MELPHALAN HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

ALKERAN HYDROCHLORIDE

Brand Name

English

L-PHENYLALANINE, 4-(BIS(2-CHLOROETHYL)AMINO)-, MONOHYDROCHLORIDE

Common Name

English

MELPHALAN HCL

Common Name

English

ALANINE, 3-(P-(BIS(2-CHLOROETHYL)AMINO)PHENYL)-, MONOHYDROCHLORIDE, L-

Common Name

English

Melphalan hydrochloride [WHO-DD]

Common Name

English

HEPZATO

Brand Name

English

PHENYLALANINE MUSTARD HYDROCHLORIDE

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

281809