Identification
NamePlitidepsin
Accession NumberDB04977
TypeSmall Molecule
GroupsInvestigational
Description

Aplidine is a compound found in tunicates which shows promise in shrinking tumors in pancreatic, stomach, bladder, and prostate cancers. The specific marine organism is Aplidium albicans. Aplidine consists of peptide molecules. In addition to the cancers mentioned above it is also under consideration as a treatment for some types of leukemia. [Wikipedia]

Structure
Thumb
Synonyms
Aplidine
Dehydrodidemnin B
plitidepsina
plitidepsine
plitidepsium
External IDs NSC638719
Product Ingredients Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AplidinNot Available
Brand mixturesNot Available
Categories
UNIIY76ID234HW
CAS number137219-37-5
WeightAverage: 1110.357
Monoisotopic: 1109.626015129
Chemical FormulaC57H87N7O15
InChI KeyUUSZLLQJYRSZIS-LXNNNBEUSA-N
InChI
InChI=1S/C57H87N7O15/c1-15-33(8)46-44(66)29-45(67)79-49(32(6)7)48(68)34(9)50(69)58-39(26-30(2)3)54(73)64-25-17-19-41(64)56(75)62(13)43(28-37-20-22-38(77-14)23-21-37)57(76)78-36(11)47(52(71)59-46)60-51(70)42(27-31(4)5)61(12)55(74)40-18-16-24-63(40)53(72)35(10)65/h20-23,30-34,36,39-44,46-47,49,66H,15-19,24-29H2,1-14H3,(H,58,69)(H,59,71)(H,60,70)/t33-,34-,36+,39-,40-,41-,42+,43-,44-,46+,47-,49-/m0/s1
IUPAC Name
(2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-10-[(2S)-butan-2-yl]-11-hydroxy-3-[(4-methoxyphenyl)methyl]-2,6,17-trimethyl-20-(2-methylpropyl)-1,4,8,13,16,18,21-heptaoxo-15-(propan-2-yl)-docosahydro-1H-pyrrolo[2,1-f]1,15-dioxa-4,7,10,20-tetraazacyclotricosan-7-yl]-4-methyl-2-{N-methyl-1-[(2S)-1-(2-oxopropanoyl)pyrrolidin-2-yl]formamido}pentanamide
SMILES
[H][[email protected]@]12CCCN1C(=O)[[email protected]](CC(C)C)NC(=O)[[email protected]@H](C)C(=O)[[email protected]@H](OC(=O)C[[email protected]](O)[[email protected]]([H])(NC(=O)[[email protected]@H](NC(=O)[[email protected]@H](CC(C)C)N(C)C(=O)[[email protected]@H]1CCCN1C(=O)C(C)=O)[[email protected]@H](C)OC(=O)[[email protected]](CC1=CC=C(OC)C=C1)N(C)C2=O)[[email protected]@H](C)CC)C(C)C
Pharmacology
Indication

Intended for the treatment of various forms of cancer.

Structured Indications Not Available
PharmacodynamicsNot Available
Mechanism of action

Aplidine inhibits the growth and induces apoptosis in MOLT-4 cells through the indirect inhibition of VEGF secretion which blocks the VEGF/VEGFR-1 autocrine loop necessary for the growth of these cells.

Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions Not Available
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Broggini M, Marchini SV, Galliera E, Borsotti P, Taraboletti G, Erba E, Sironi M, Jimeno J, Faircloth GT, Giavazzi R, D'Incalci M: Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4. Leukemia. 2003 Jan;17(1):52-9. [PubMed:12529660 ]
  2. Depenbrock H, Peter R, Faircloth GT, Manzanares I, Jimeno J, Hanauske AR: In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells. Br J Cancer. 1998 Sep;78(6):739-44. [PubMed:9743292 ]
  3. Sparidans RW, Kettenes-van den Bosch JJ, van Tellingen O, Nuyen B, Henrar RE, Jimeno JM, Faircloth G, Floriano P, Rinehart KL, Beijnen JH: Bioanalysis of aplidine, a new marine antitumoral depsipeptide, in plasma by high-performance liquid chromatography after derivatization with trans-4-hydrazino-2-stilbazole. J Chromatogr B Biomed Sci Appl. 1999 Jun 11;729(1-2):43-53. [PubMed:10410926 ]
  4. Celli N, Gallardo AM, Rossi C, Zucchetti M, D'Incalci M, Rotilio D: Analysis of aplidine (dehydrodidemnin B), a new marine-derived depsipeptide, in rat biological fluids by liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl. 1999 Aug 20;731(2):335-43. [PubMed:10510788 ]
  5. Nuijen B, Bouma M, Henrar RE, Floriano P, Jimeno JM, Talsma H, Kettenes-van den Bosch JJ, Heck AJ, Bult A, Beijnen JH: Pharmaceutical development of a parenteral lyophilized formulation of the novel antitumor agent aplidine. PDA J Pharm Sci Technol. 2000 May-Jun;54(3):193-208. [PubMed:10927911 ]
  6. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [PubMed:16633717 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAdvanced Solid Tumors / Malignant Lymphomas1
1RecruitingOtherMultiple Myeloma (MM)1
2CompletedTreatmentAgnogenic Myeloid Metaplasia1
2CompletedTreatmentLeukemias / Malignant Lymphomas1
2CompletedTreatmentMultiple Myeloma (MM)1
2RecruitingTreatmentMalignant Lymphomas1
2RecruitingTreatmentMultiple Myeloma (MM)1
2TerminatedTreatmentAdult Patients With Unresectable Locally Advanced or Metastatic, Relapsed/Refractory Dedifferentiated Liposarcoma1
2TerminatedTreatmentProstate Cancer1
3Active Not RecruitingTreatmentRelapsed/Refractory Multiple Myeloma1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0201 mg/mLALOGPS
logP3.07ALOGPS
logP3.98ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)10.91ChemAxon
pKa (Strongest Basic)-3.1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count13ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area284.74 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity288.14 m3·mol-1ChemAxon
Polarizability117.17 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.5955
Blood Brain Barrier-0.9925
Caco-2 permeable-0.8093
P-glycoprotein substrateSubstrate0.871
P-glycoprotein inhibitor INon-inhibitor0.5983
P-glycoprotein inhibitor IINon-inhibitor0.6832
Renal organic cation transporterNon-inhibitor0.9272
CYP450 2C9 substrateNon-substrate0.8754
CYP450 2D6 substrateNon-substrate0.8752
CYP450 3A4 substrateSubstrate0.6458
CYP450 1A2 substrateNon-inhibitor0.9633
CYP450 2C9 inhibitorNon-inhibitor0.8868
CYP450 2D6 inhibitorNon-inhibitor0.8675
CYP450 2C19 inhibitorNon-inhibitor0.8931
CYP450 3A4 inhibitorNon-inhibitor0.7351
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9601
Ames testNon AMES toxic0.815
CarcinogenicityNon-carcinogens0.9054
BiodegradationNot ready biodegradable0.8974
Rat acute toxicity2.8308 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9549
hERG inhibition (predictor II)Non-inhibitor0.6708
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as cyclic depsipeptides. These are natural or synthetic compounds having sequences of amino and hydroxy carboxylic acid residues (usually α-amino and α-hydroxy acids) connected in a ring. The residues are commonly but not necessarily regularly alternating.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentCyclic depsipeptides
Alternative ParentsLeucine and derivatives / Macrolide lactams / Macrolactams / N-acyl-alpha amino acids and derivatives / Alpha amino acid esters / Proline and derivatives / Alpha amino acid amides / N-acylpyrrolidines / Anisoles / Methoxybenzenes
SubstituentsCyclic depsipeptide / Macrolide lactam / Leucine or derivatives / Macrolactam / Alpha-amino acid ester / Proline or derivatives / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Alpha-amino acid or derivatives / Phenoxy compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Uniprot Name:
Cytochrome P450 3A4
Molecular Weight:
57342.67 Da
References
  1. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [PubMed:16633717 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Steroid hydroxylase activity
Specific Function:
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.
Gene Name:
CYP2A6
Uniprot ID:
P11509
Uniprot Name:
Cytochrome P450 2A6
Molecular Weight:
56501.005 Da
References
  1. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [PubMed:16633717 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Steroid hydroxylase activity
Specific Function:
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Uniprot Name:
Cytochrome P450 2E1
Molecular Weight:
56848.42 Da
References
  1. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [PubMed:16633717 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Leukotriene-b4 20-monooxygenase activity
Specific Function:
Catalyzes the omega- and (omega-1)-hydroxylation of various fatty acids such as laurate, myristate and palmitate. Has little activity toward prostaglandins A1 and E1. Oxidizes arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE).
Gene Name:
CYP4A11
Uniprot ID:
Q02928
Uniprot Name:
Cytochrome P450 4A11
Molecular Weight:
59347.31 Da
References
  1. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [PubMed:16633717 ]
Drug created on October 21, 2007 16:23 / Updated on September 01, 2017 11:23