Lonidamine

This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Name
Lonidamine
Accession Number
DB06266  (DB03762)
Type
Small Molecule
Groups
Investigational
Description

Lonidamine (LND) is a drug that interferes with energy metabolism of cancer cells, principally inhibiting aerobic glycolytic activity, by its effect on mitochondrially-bound hexokinase (HK). In such way LND could impair energy-requiring processes, as recovery from potentially lethal damage, induced by radiation treatment and by some cytotoxic drugs.

Structure
Thumb
Synonyms
  • 1-(2,4-dichlorbenzyl)-indazole-3-carboxylic acid
  • DICA
  • diclondazolic acid
  • Doridamina
  • Lonidamin
  • lonidamina
  • lonidaminum
Categories
UNII
U78804BIDR
CAS number
50264-69-2
Weight
Average: 321.158
Monoisotopic: 320.011932988
Chemical Formula
C15H10Cl2N2O2
InChI Key
WDRYRZXSPDWGEB-UHFFFAOYSA-N
InChI
InChI=1S/C15H10Cl2N2O2/c16-10-6-5-9(12(17)7-10)8-19-13-4-2-1-3-11(13)14(18-19)15(20)21/h1-7H,8H2,(H,20,21)
IUPAC Name
1-[(2,4-dichlorophenyl)methyl]-1H-indazole-3-carboxylic acid
SMILES
OC(=O)C1=NN(CC2=C(Cl)C=C(Cl)C=C2)C2=C1C=CC=C2

Pharmacology

Indication

Investigated for use/treatment in benign prostatic hyperplasia, prostate disorders, and cancer/tumors (unspecified).

Structured Indications
Not Available
Pharmacodynamics
Not Available
Mechanism of action

Lonidamine is an orally administered small molecule that inhibits glycolysis by the inactivation of hexokinase. Hexokinase is an enzyme that catalyzes glucose, the first step in glycolysis. The inhibition of hexokinase by lonidamine is well established. In addition, there is evidence that lonidamine may increase programmed cell death. This stems from the observation that mitochondria and mitochondria-bound hexokinase are crucial for induction of apoptosis; agents that directly effect mitochondria may, therefore, trigger apoptosis. Indeed, in vitro models with lonidamine exhibit the hallmarks of apoptosis, including mitochondrial membrane depolarization, release of cytochrome C, phosphatidylserine externalization, and DNA fragmentation. [PMID: 16986057]

TargetActionsOrganism
UCystic fibrosis transmembrane conductance regulatorNot AvailableHuman
UHexokinase-1Not 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
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Lonidamine.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Lonidamine.Experimental
AncestimThe risk or severity of cytotoxicity can be increased when Ancestim is combined with Lonidamine.Approved, Investigational, Withdrawn
BevacizumabBevacizumab may increase the cardiotoxic activities of Lonidamine.Approved, Investigational
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Lonidamine.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Lonidamine.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Lonidamine.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Lonidamine.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Lonidamine.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Lonidamine.Approved
GitoformateGitoformate may decrease the cardiotoxic activities of Lonidamine.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Lonidamine.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Lonidamine.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Lonidamine.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Lonidamine.Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Lonidamine.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Lonidamine.Experimental
TipiracilThe therapeutic efficacy of Lonidamine can be decreased when used in combination with Tipiracil.Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Lonidamine.Approved, Investigational
Food Interactions
Not Available

References

General References
  1. Carapella CM, Paggi MG, Calvosa F, Cattani F, Jandolo B, Mastrostefano R, Raus L, Riccio A: Lonidamine in the combined treatment of malignant gliomas. A randomized study. J Neurosurg Sci. 1990 Jul-Dec;34(3-4):261-4. [PubMed:2098504]
  2. Brawer MK: Lonidamine: basic science and rationale for treatment of prostatic proliferative disorders. Rev Urol. 2005;7 Suppl 7:S21-6. [PubMed:16986057]
External Links
KEGG Drug
D07257
PubChem Compound
39562
ChemSpider
36170
BindingDB
59775
ChEBI
50138
ChEMBL
CHEMBL1257030
Wikipedia
Lonidamine
ATC Codes
L01XX07 — Lonidamine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2TerminatedTreatmentBenign Prostatic Hyperplasia (BPH)1
3TerminatedTreatmentBenign Prostatic Hyperplasia (BPH) / Enlarged Prostate1

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)207 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility0.00904 mg/mLALOGPS
logP3.9ALOGPS
logP4.4ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)3.12ChemAxon
pKa (Strongest Basic)-1.5ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area55.12 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity92.4 m3·mol-1ChemAxon
Polarizability30.34 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9547
Caco-2 permeable+0.5242
P-glycoprotein substrateNon-substrate0.7804
P-glycoprotein inhibitor INon-inhibitor0.9191
P-glycoprotein inhibitor IIInhibitor0.5
Renal organic cation transporterNon-inhibitor0.5803
CYP450 2C9 substrateNon-substrate0.7304
CYP450 2D6 substrateNon-substrate0.8372
CYP450 3A4 substrateNon-substrate0.5083
CYP450 1A2 substrateNon-inhibitor0.9031
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.923
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8144
BiodegradationNot ready biodegradable0.9966
Rat acute toxicity2.2451 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9221
hERG inhibition (predictor II)Non-inhibitor0.8407
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0pb9-0907000000-8c1504c16c85b7a25213
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0bt9-2900000000-7658029adb35b1dd05c8

Taxonomy

Description
This compound belongs to the class of organic compounds known as indazoles. These are compounds containing an indazole, which is structurally characterized by a pyrazole fused to a benzene.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzopyrazoles
Sub Class
Indazoles
Direct Parent
Indazoles
Alternative Parents
Pyrazole carboxylic acids and derivatives / Dichlorobenzenes / Aryl chlorides / Heteroaromatic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds
show 3 more
Substituents
Benzopyrazole / Indazole / Pyrazole-3-carboxylic acid or derivatives / Pyrazole-5-carboxylic acid or derivatives / 1,3-dichlorobenzene / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid, dichlorobenzene, indazoles (CHEBI:50138)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Pdz domain binding
Specific Function
Involved in the transport of chloride ions. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the SLC4A7 transporter. Can inhibit the chloride channel activity of ANO...
Gene Name
CFTR
Uniprot ID
P13569
Uniprot Name
Cystic fibrosis transmembrane conductance regulator
Molecular Weight
168139.895 Da
References
  1. Sommer D, Bogdan R, Berger J, Peters DM, Morty RE, Clauss WG, Fronius M: CFTR-dependent Cl- secretion in Xenopus laevis lung epithelium. Respir Physiol Neurobiol. 2007 Aug 15;158(1):97-106. Epub 2007 Apr 5. [PubMed:17490919]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Mannokinase activity
Specific Function
Not Available
Gene Name
HK1
Uniprot ID
P19367
Uniprot Name
Hexokinase-1
Molecular Weight
102485.1 Da
References
  1. Brawer MK: Lonidamine: basic science and rationale for treatment of prostatic proliferative disorders. Rev Urol. 2005;7 Suppl 7:S21-6. [PubMed:16986057]

Drug created on March 19, 2008 10:20 / Updated on December 08, 2017 12:21