Plitidepsin

Identification

Name
Plitidepsin
Accession Number
DB04977
Type
Small Molecule
Groups
Investigational
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
International/Other Brands
Aplidin
Categories
UNII
Y76ID234HW
CAS number
137219-37-5
Weight
Average: 1110.357
Monoisotopic: 1109.626015129
Chemical Formula
C57H87N7O15
InChI Key
UUSZLLQJYRSZIS-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
Pharmacodynamics
Not 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.

Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

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
KEGG Compound
C16862
PubChem Compound
9812534
PubChem Substance
175426924
ChemSpider
24687645
ChEBI
90205
ChEMBL
CHEMBL451930
Wikipedia
Plitidepsin

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

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not 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
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Peptidomimetics
Sub Class
Depsipeptides
Direct Parent
Cyclic depsipeptides
Alternative Parents
Leucine and derivatives / Macrolide lactams / Macrolactams / N-acyl-alpha amino acids and derivatives / Proline and derivatives / Alpha amino acid esters / Alpha amino acid amides / Methoxybenzenes / Pyrrolidinecarboxamides / N-acylpyrrolidines
show 20 more
Substituents
Cyclic depsipeptide / Macrolide lactam / Leucine or derivatives / N-acyl-alpha amino acid or derivatives / Macrolactam / Proline or derivatives / Alpha-amino acid ester / Alpha-amino acid amide / Alpha-amino acid or derivatives / Anisole
show 40 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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 react...
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. Const...
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 ...
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 2...
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 November 09, 2017 03:49