Tridolgosir

Identification

Name
Tridolgosir
Accession Number
DB02034  (EXPT02983, DB06425)
Type
Small Molecule
Groups
Experimental
Description

An indolizidine alkaloid from the plant Swainsona canescens that is a potent alpha-mannosidase inhibitor. Swainsonine also exhibits antimetastatic, antiproliferative, and immunomodulatory activity.

Structure
Thumb
Synonyms
  • (1S,2R,8R,8AR)-octahydro-1,2,8-indolizinetriol
  • Swainosine
Product Ingredients
IngredientUNIICASInChI Key
Tridolgosir hydrochloride78KR51ES9B214462-68-7LIRVFCZWYJVKCV-XNJRRJNCSA-N
Categories
Not Available
UNII
RSY4RK37KQ
CAS number
72741-87-8
Weight
Average: 173.2096
Monoisotopic: 173.105193351
Chemical Formula
C8H15NO3
InChI Key
FXUAIOOAOAVCGD-WCTZXXKLSA-N
InChI
InChI=1S/C8H15NO3/c10-5-2-1-3-9-4-6(11)8(12)7(5)9/h5-8,10-12H,1-4H2/t5-,6-,7-,8-/m1/s1
IUPAC Name
(1S,2R,8R,8aR)-octahydroindolizine-1,2,8-triol
SMILES

Pharmacology

Indication
Not Available
Structured Indications
Not Available
Pharmacodynamics
Not Available
Mechanism of action

Tridolgosir competitively inhibits the alpha manosidase II (alphaMII), which processes N linked carbohydrates of newly synthesized glycoproteins passing through the Golgi apparatus to the cell surface. Highly branched carbohydrate structures are created which bind to Lectin-phytohemagglutinin (L-PHA) and are subsequently expressed in different tumor types which results in metastatic phenotype, which is correlated with an increased aggressiveness in animals and causes other human malignancies. Inhibition of alphaMII reduces carbohydrates that bind to L-PHA, reducing aggressiveness, metastatic phenotype cells, slows tumor growth, and increases“hybrid type” carbohydrates on the cell surface. Hybrid type carbohydrates may increase cytokine activation of lymphocytes, increasing tumor susceptibility to lymphokine activated and natural killer cells.

TargetActionsOrganism
UAlpha-mannosidase 2Not AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

Synthesis Reference

William H. Pearson, Erik J. Hembre, "Method for preparing swainsonine." U.S. Patent US5919952, issued December, 1986.

US5919952
General References
  1. Shaheen PE, Stadler W, Elson P, Knox J, Winquist E, Bukowski RM: Phase II study of the efficacy and safety of oral GD0039 in patients with locally advanced or metastatic renal cell carcinoma. Invest New Drugs. 2005 Dec;23(6):577-81. [PubMed:16034517]
External Links
KEGG Compound
C10173
PubChem Compound
51683
PubChem Substance
46506581
ChemSpider
46788
BindingDB
50168995
ChEBI
9367
ChEMBL
CHEMBL371197
HET
SWA
Wikipedia
Swainsonine
PDB Entries
1hww / 2ww0 / 2ww2 / 2wyi / 3blb

Clinical Trials

Clinical Trials
Not Available

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)143-144 °CNot Available
Predicted Properties
PropertyValueSource
Water Solubility1320.0 mg/mLALOGPS
logP-1.5ALOGPS
logP-1.4ChemAxon
logS0.88ALOGPS
pKa (Strongest Acidic)13.28ChemAxon
pKa (Strongest Basic)9.47ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area63.93 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity43.12 m3·mol-1ChemAxon
Polarizability17.84 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9652
Blood Brain Barrier+0.5273
Caco-2 permeable-0.5141
P-glycoprotein substrateSubstrate0.6622
P-glycoprotein inhibitor INon-inhibitor0.8542
P-glycoprotein inhibitor IINon-inhibitor0.9732
Renal organic cation transporterNon-inhibitor0.6424
CYP450 2C9 substrateNon-substrate0.8769
CYP450 2D6 substrateNon-substrate0.6593
CYP450 3A4 substrateNon-substrate0.5136
CYP450 1A2 substrateNon-inhibitor0.7861
CYP450 2C9 inhibitorNon-inhibitor0.9292
CYP450 2D6 inhibitorNon-inhibitor0.9075
CYP450 2C19 inhibitorNon-inhibitor0.9214
CYP450 3A4 inhibitorNon-inhibitor0.9972
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9921
Ames testNon AMES toxic0.7576
CarcinogenicityNon-carcinogens0.9722
BiodegradationNot ready biodegradable0.9773
Rat acute toxicity2.3774 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6501
hERG inhibition (predictor II)Non-inhibitor0.8976
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
GC-MS Spectrum - GC-MS (3 TMS)GC-MSsplash10-014i-2911110000-6a7c4a62604e701b490d
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 indolizidines. These are polycyclic compounds containing an indolizidine, which is a bicyclic heterocycle containing a saturated six-member ring fused to a saturated five-member ring, one of the bridging atoms being nitrogen.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indolizidines
Sub Class
Not Available
Direct Parent
Indolizidines
Alternative Parents
Piperidines / N-alkylpyrrolidines / Trialkylamines / Secondary alcohols / 1,2-aminoalcohols / Polyols / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Indolizidine / Piperidine / N-alkylpyrrolidine / Pyrrolidine / Tertiary aliphatic amine / Tertiary amine / Secondary alcohol / 1,2-aminoalcohol / Azacycle / Polyol
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
indolizidine alkaloid (CHEBI:9367) / Indolizidine alkaloids (C10173)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Catalyzes the first committed step in the biosynthesis of complex N-glycans. It controls conversion of high mannose to complex N-glycans; the final hydrolytic step in the N-glycan maturation pathway.
Gene Name
MAN2A1
Uniprot ID
Q16706
Uniprot Name
Alpha-mannosidase 2
Molecular Weight
131139.485 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. [PubMed: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. [PubMed:17016423]
  3. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235]

Drug created on June 13, 2005 07:24 / Updated on November 09, 2017 03:08