Sodium stibogluconate

Identification

Name
Sodium stibogluconate
Accession Number
DB05630
Type
Small Molecule
Groups
Approved, Investigational
Description

Sodium stibogluconate is a medicine used to treat leishmaniasis and is only available for administration by injection. It belongs to the class of medicines known as the pentavalent antimonials. Sodium stibogluconate is sold in the UK as Pentostam (manufactured by GlaxoSmithKline). Widespread resistance has limited the utility of sodium stibogluconate, and in many parts of the world, amphotericin or miltefosine are used instead. It is also being investigated as an anti-tumor agent.

Structure
Thumb
Synonyms
  • Antimony (v) derivative OF sodium gluconate
  • Antimony sodium gluconate
  • Estibogluconato sodico
  • Myostibin
  • Natrii stibogluconas
  • Sodium stibogluconate
  • Stibanate
  • Stibanose
  • Stibatin
  • Stibinol
  • Stibogluconate de sodium
  • Trisodium 1-{[3-carboxylato-5-(1,2-dihydroxyethyl)-1-hydroxy-2,6,7-trioxa-1lambda(5)-stibabicyclo[2.2.1]hept-1-yl]oxy}-5-(1,2-dihydroxyethyl)-1-oxido-2,6,7-trioxa-1lambda(5)-stibabicyclo[2.2.1]heptane-3-carboxylate nonahydrate
International/Other Brands
Pentostam (GlaxoSmithKline)
Categories
UNII
APJ6285Y89
CAS number
16037-91-5
Weight
Average: 907.88
Monoisotopic: 905.918601405
Chemical Formula
C12H35Na3O26Sb2
InChI Key
YQDGWZZYGYKDLR-UZVLBLASSA-K
InChI
InChI=1S/2C6H9O7.3Na.10H2O.2O.2Sb/c2*7-1-2(8)3(9)4(10)5(11)6(12)13;;;;;;;;;;;;;;;;;/h2*2-5,7-8H,1H2,(H,12,13);;;;10*1H2;;;;/q2*-3;3*+1;;;;;;;;;;;;-1;+3;+4/p-3/t2*2-,3-,4+,5-;;;;;;;;;;;;;;;;;/m11................./s1
IUPAC Name
trisodium (3R,4S,5R)-1-{[(3R,4S,5R)-3-carboxylato-5-[(1R)-1,2-dihydroxyethyl]-1-oxido-2,6,7-trioxa-1-stibabicyclo[2.2.1]heptan-1-yl]oxy}-5-[(1R)-1,2-dihydroxyethyl]-1-hydroxy-2,6,7-trioxa-1-stibabicyclo[2.2.1]heptane-3-carboxylate nonahydrate
SMILES
O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[H][C@@]1(O[Sb]2(O)(O[Sb]34([O-])O[C@@H](C([O-])=O)[C@@]([H])(O3)[C@]([H])(O4)[C@H](O)CO)O[C@@H](C([O-])=O)[C@@]1([H])O2)[C@H](O)CO

Pharmacology

Indication

For the treatment of various types of a protozoal infection called leishmaniasis, which may result from sandfly bites in tropical and temperate parts of the world. Also investigated for use/treatment in cancer/tumors (unspecified) and solid tumors.

Pharmacodynamics

The mode of action of sodium stibogluconate is not clearly understood. In vitro exposure of amastigotes to 500 mg pentavalent antimony/ml results in a greater than 50% decrease in parasite DNA, RNA protein and purine nucleoside triphosphate levels. It has been postulated that the reduction in ATP (adenosine triphosphate) and GTP (guanosine triphosphate) synthesis contributes to decreased macromolecular synthesis.

Mechanism of action

Sodium stibogluconate directly inhibits DNA topoisomerase I leading to inhibition of both DNA replication and transcription.

TargetActionsOrganism
ADNA topoisomerase 1
inhibitor
Human
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

The main symptoms of antimony overdosage are gastro-intestinal disturbances (nausea, vomiting and severe diarrhoea). Haemorrhagic nephritis and hepatitis may also occur.

Affected organisms
  • Humans and other mammals
  • Protozoa
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AmodiaquineThe serum concentration of Sodium stibogluconate can be decreased when it is combined with Amodiaquine.
PrimaquineThe serum concentration of Sodium stibogluconate can be decreased when it is combined with Primaquine.
TafenoquineThe serum concentration of Sodium stibogluconate can be decreased when it is combined with Tafenoquine.
Food Interactions
Not Available

References

General References
  1. Murray HW, Berman JD, Davies CR, Saravia NG: Advances in leishmaniasis. Lancet. 2005 Oct 29-Nov 4;366(9496):1561-77. [PubMed:16257344]
External Links
Human Metabolome Database
HMDB15617
KEGG Drug
D00582
PubChem Compound
56927674
PubChem Substance
99443233
ChemSpider
27471272
ChEBI
28148
ChEMBL
CHEMBL2079699
Therapeutic Targets Database
DCL000001
PharmGKB
PA164743129
Wikipedia
Sodium_stibogluconate
ATC Codes
P01CB02 — Sodium stibogluconate

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCancer, Advanced / Tumors, Solid1
1CompletedTreatmentStage IV Melanoma1
1TerminatedTreatmentCancers1
1TerminatedTreatmentMyelodysplastic Syndromes1
1, 2CompletedTreatmentLeishmaniasis1
2CompletedTreatmentLeishmaniasis1
2CompletedTreatmentLeishmaniasis, Cutaneous2
2CompletedTreatmentPrimary Visceral Leishmaniasis1
2CompletedTreatmentWound Healing1
2WithdrawnTreatmentCancer, Advanced / Tumors, Solid1
3CompletedTreatmentVisceral Leishmaniasis1
3RecruitingTreatmentVisceral Leishmaniasis1
4CompletedTreatmentLeishmaniasis, Cutaneous1
Not AvailableAvailableNot AvailableLeishmaniasis, Cutaneous / Mucocutaneous Leishmaniasis1
Not AvailableUnknown StatusNot AvailableLeishmaniasis, Cutaneous1

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
logP-3.4ChemAxon
pKa (Strongest Acidic)2.29ChemAxon
pKa (Strongest Basic)-3ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count17ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area269.08 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity96.29 m3·mol-1ChemAxon
Polarizability39.78 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9877
Blood Brain Barrier+0.7918
Caco-2 permeable-0.6847
P-glycoprotein substrateNon-substrate0.5879
P-glycoprotein inhibitor INon-inhibitor0.7637
P-glycoprotein inhibitor IINon-inhibitor0.9641
Renal organic cation transporterNon-inhibitor0.8876
CYP450 2C9 substrateNon-substrate0.8656
CYP450 2D6 substrateNon-substrate0.8282
CYP450 3A4 substrateNon-substrate0.5946
CYP450 1A2 substrateNon-inhibitor0.8279
CYP450 2C9 inhibitorNon-inhibitor0.8578
CYP450 2D6 inhibitorNon-inhibitor0.8796
CYP450 2C19 inhibitorNon-inhibitor0.79
CYP450 3A4 inhibitorNon-inhibitor0.937
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9436
Ames testNon AMES toxic0.72
CarcinogenicityNon-carcinogens0.8598
BiodegradationNot ready biodegradable0.5984
Rat acute toxicity2.4267 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8894
hERG inhibition (predictor II)Non-inhibitor0.7668
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as dicarboxylic acids and derivatives. These are organic compounds containing exactly two carboxylic acid groups.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Dicarboxylic acids and derivatives
Direct Parent
Dicarboxylic acids and derivatives
Alternative Parents
Secondary alcohols / Organic antimony salts / Carboxylic acid salts / Oxacyclic compounds / Metalloheterocyclic compounds / Carboxylic acids / Primary alcohols / Organic zwitterions / Organic sodium salts / Organic oxides
show 2 more
Substituents
Dicarboxylic acid or derivatives / Carboxylic acid salt / Secondary alcohol / Organic antimony salt / Organic alkali metal salt / Oxacycle / Organic metal salt / Organic metalloid salt / Carboxylic acid / Organoheterocyclic compound
show 12 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
D-gluconate adduct (CHEBI:28148)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Poly(a) rna binding
Specific Function
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a singl...
Gene Name
TOP1
Uniprot ID
P11387
Uniprot Name
DNA topoisomerase 1
Molecular Weight
90725.19 Da
References
  1. Walker J, Saravia NG: Inhibition of Leishmania donovani promastigote DNA topoisomerase I and human monocyte DNA topoisomerases I and II by antimonial drugs and classical antitopoisomerase agents. J Parasitol. 2004 Oct;90(5):1155-62. [PubMed:15562618]
  2. Chakraborty AK, Majumder HK: Mode of action of pentavalent antimonials: specific inhibition of type I DNA topoisomerase of Leishmania donovani. Biochem Biophys Res Commun. 1988 Apr 29;152(2):605-11. [PubMed:2835038]
  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 November 18, 2007 11:26 / Updated on October 01, 2018 14:02