Identification

Name
Plicamycin
Accession Number
DB06810
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Plicamycin is an antineoplastic antibiotic produced by Streptomyces plicatus. It has been used in the treatment of testicular cancer, Paget's disease of bone, and, rarely, the management of hypercalcemia. The manufacturer discontinued plicamycin in 2000.

Structure
Thumb
Synonyms
  • Aureolic acid
  • Mithramycin
  • Mithramycine
  • Mithramycinum
  • Plicamycin
  • Plicamycine
  • Plicamycinum
External IDs
A-2371 / ANTIBIOTIC LA-7017 / LA-7017 / NSC-24559 / PA-144
International/Other Brands
Mithracin (Pfizer)
Categories
UNII
NIJ123W41V
CAS number
18378-89-7
Weight
Average: 1085.1454
Monoisotopic: 1084.47265336
Chemical Formula
C52H76O24
InChI Key
CFCUWKMKBJTWLW-BKHRDMLASA-N
InChI
InChI=1S/C52H76O24/c1-18-29(72-34-14-30(43(58)21(4)68-34)73-33-13-28(54)42(57)20(3)67-33)12-26-10-25-11-27(49(66-9)48(63)41(56)19(2)53)50(47(62)39(25)46(61)38(26)40(18)55)76-36-16-31(44(59)23(6)70-36)74-35-15-32(45(60)22(5)69-35)75-37-17-52(8,65)51(64)24(7)71-37/h10,12,19-24,27-28,30-37,41-45,49-51,53-61,64-65H,11,13-17H2,1-9H3/t19-,20-,21-,22-,23-,24-,27+,28-,30-,31-,32-,33+,34+,35+,36+,37+,41+,42-,43-,44-,45+,49+,50+,51-,52+/m1/s1
IUPAC Name
(2S,3S)-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-2-{[(2S,4R,5R,6R)-4-{[(2S,4R,5S,6R)-4-{[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]oxy}-6-{[(2S,4R,5R,6R)-4-{[(2S,4R,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]oxy}-8,9-dihydroxy-7-methyl-1,2,3,4-tetrahydroanthracen-1-one
SMILES
CO[C@@H]([C@@H]1CC2=CC3=CC(O[C@H]4C[C@@H](O[C@H]5C[C@@H](O)[C@H](O)[C@@H](C)O5)[C@H](O)[C@@H](C)O4)=C(C)C(O)=C3C(O)=C2C(=O)[C@H]1O[C@H]1C[C@@H](O[C@H]2C[C@@H](O[C@H]3C[C@](C)(O)[C@H](O)[C@@H](C)O3)[C@@H](O)[C@@H](C)O2)[C@H](O)[C@@H](C)O1)C(=O)[C@@H](O)[C@@H](C)O

Pharmacology

Indication

For the treatment of testicular cancer, as well as hypercalcemia and hypercalciuria associated with a variety of advanced forms of cancer.

Pharmacodynamics

Plicamycin is lethal to Hela cells in 48 hours at concentrations as low as 0.5 micrograms per milliliter of tissue culture medium. Plicamycin has shown significant anti-tumor activity against experimental leukemia in mice when administered intraperitoneally.

Mechanism of action

Plicamycin is presumed to inhibit cellular and enzymic RNA synthesis by forming a complex with DNA. Plicamycin may also lower calcium serum levels by inhibiting the effect of parathyroid hormone upon osteoclasts or by blocking the hypercalcemic action of pharmacologic doses of vitamin D.

TargetActionsOrganism
ADNA
antagonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

There is no evidence of protein binding, nor is there any evidence of metabolism of the carbohydrate moiety of the drug to carbon dioxide and water with loss through respiration.

Metabolism
Not Available
Route of elimination

Radioautography studies with 3H-labeled plicamycin in mice show that the greatest concentrations of the isotope are in the Kupffer cells of the liver and cells of the renal tubules. Plicamycin is rapidly cleared from the blood within the first 2 hours and excretion is also rapid. 67% percent of measured excretion occurs within 4 hours, 75% within 8 hours, and 90% is recovered in the first 24 hours after injection.

Half life
Not Available
Clearance
Not Available
Toxicity

The most important form of toxicity associated with the use of plicamycin consists of a dose-related bleeding syndrome which usually begins with an episode of epistaxis. Plicamycin crosses the blood-brain barrier; the concentration found in brain tissue is low but it persists longer than in other tissues.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

Synthesis Reference

Jurgen Rohr, Lily Remsing, Mohammad Nur-e-Alam, Jose Salas, Carmen Mendez, Alfredo Brana, Ana Gonzalez, "Derivatives of mithramycin and methods of making and uses thereof." U.S. Patent US20050192432, issued September 01, 2005.

US20050192432
General References
  1. Wohlert SE, Kunzel E, Machinek R, Mendez C, Salas JA, Rohr J: The structure of mithramycin reinvestigated. J Nat Prod. 1999 Jan;62(1):119-21. [PubMed:9917296]
External Links
Human Metabolome Database
HMDB0015682
KEGG Drug
D00468
KEGG Compound
C12389
PubChem Compound
163659
PubChem Substance
99443298
ChemSpider
143544
ChEBI
31856
ChEMBL
CHEMBL1237054
PharmGKB
PA165958411
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Plicamycin
ATC Codes
L01DC02 — Plicamycin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2SuspendedTreatmentMesothelioma / Neoplasms, Esophageal / Neoplasms, Germ Cell and Embryonal / Neoplasms, Lung / Thymus Neoplasms1
1, 2TerminatedTreatmentEwing's Sarcoma (ES) / Sarcomas1
2RecruitingTreatmentCancer, Breast / Esophageal Cancers / Lung Cancers / Mesothelioma / Neoplasms, Gastrointestinal1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)181.5 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility1.3 mg/mLALOGPS
logP-0.23ALOGPS
logP2.07ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)8.49ChemAxon
pKa (Strongest Basic)-3.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count24ChemAxon
Hydrogen Donor Count11ChemAxon
Polar Surface Area358.2 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity257.01 m3·mol-1ChemAxon
Polarizability114.41 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.6522
Blood Brain Barrier-0.7202
Caco-2 permeable-0.7222
P-glycoprotein substrateSubstrate0.8084
P-glycoprotein inhibitor INon-inhibitor0.7246
P-glycoprotein inhibitor IINon-inhibitor0.7979
Renal organic cation transporterNon-inhibitor0.9474
CYP450 2C9 substrateNon-substrate0.829
CYP450 2D6 substrateNon-substrate0.8772
CYP450 3A4 substrateSubstrate0.6129
CYP450 1A2 substrateNon-inhibitor0.6673
CYP450 2C9 inhibitorNon-inhibitor0.9692
CYP450 2D6 inhibitorNon-inhibitor0.9228
CYP450 2C19 inhibitorNon-inhibitor0.9555
CYP450 3A4 inhibitorNon-inhibitor0.8839
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9814
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9528
BiodegradationNot ready biodegradable0.9779
Rat acute toxicity3.0601 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9888
hERG inhibition (predictor II)Non-inhibitor0.8029
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 oligosaccharides. These are carbohydrates made up of 3 to 10 monosaccharide units linked to each other through glycosidic bonds.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbohydrates and carbohydrate conjugates
Direct Parent
Oligosaccharides
Alternative Parents
Anthracenes / Naphthols and derivatives / O-glycosyl compounds / Tetralins / Aryl alkyl ketones / 1-hydroxy-4-unsubstituted benzenoids / Oxanes / Beta-hydroxy ketones / Acyloins / Vinylogous acids
show 8 more
Substituents
Oligosaccharide / Anthracene / Glycosyl compound / 1-naphthol / O-glycosyl compound / Tetralin / Aryl ketone / Aryl alkyl ketone / 1-hydroxy-4-unsubstituted benzenoid / Benzenoid
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
anthracycline antibiotic, carbohydrate-containing antibiotic, aureolic acid (CHEBI:31856)

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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. Fox KR, Howarth NR: Investigations into the sequence-selective binding of mithramycin and related ligands to DNA. Nucleic Acids Res. 1985 Dec 20;13(24):8695-714. [PubMed:2934687]
  2. Lombo F, Menendez N, Salas JA, Mendez C: The aureolic acid family of antitumor compounds: structure, mode of action, biosynthesis, and novel derivatives. Appl Microbiol Biotechnol. 2006 Nov;73(1):1-14. Epub 2006 Sep 30. [PubMed:17013601]
  3. Hampshire AJ, Fox KR: The effects of local DNA sequence on the interaction of ligands with their preferred binding sites. Biochimie. 2008 Jul;90(7):988-98. doi: 10.1016/j.biochi.2008.01.001. Epub 2008 Jan 11. [PubMed:18226601]

Drug created on September 14, 2010 10:21 / Updated on November 02, 2018 06:21