Details
Stereochemistry | ACHIRAL |
Molecular Formula | C15H10Cl2N2O2 |
Molecular Weight | 321.158 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
OC(=O)C1=NN(CC2=C(Cl)C=C(Cl)C=C2)C3=C1C=CC=C3
InChI
InChIKey=WDRYRZXSPDWGEB-UHFFFAOYSA-N
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)
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/27497601Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/12814259 | https://www.ncbi.nlm.nih.gov/pubmed/12972521 | https://www.ncbi.nlm.nih.gov/pubmed/7285632 | https://www.ncbi.nlm.nih.gov/pubmed/26831515
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27497601
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/12814259 | https://www.ncbi.nlm.nih.gov/pubmed/12972521 | https://www.ncbi.nlm.nih.gov/pubmed/7285632 | https://www.ncbi.nlm.nih.gov/pubmed/26831515
Lonidamine is a derivative of the indazole-3-carboxylic acid, with limited antineoplastic activity as a single agent but with exceptional potential in modulating the activities of conventional chemotherapeutic agents such as N-mustard alkylating agents and anthracyclines as well as hyperthermia, radiation therapy and photodynamic therapy. The most critical property of Lonidamine is its selective activity against a broad range of tumors with little to no effect on normal tissues provided that doses are below a threshold level of ~400 mg/m^2 (oral or i.v. doses). Selective effects of Lonidamine on tumors compared to other potential targets probably result from the dependence of most tumors on glycolytic metabolism, but the exact mechanism of specificity is still not fully known. Current evidence indicates that Lonidamine inhibits lactate export by the proton-linked monocarboxylate transporter(s) (MCT) and pyruvate uptake into mitochondria via the mitochondrial pyruvate carrier (MPC), whereas inhibition of respiration involves both diminished mitochondrial uptake of pyruvate via the MPC as well as inhibition of the mitochondrial electron-transport chain at Complex II and perhaps also Complex I, in both instances at the ubiquinone reduction step. There is also evidence that the drug may indirectly inhibit hexokinase as well as possibly other glycolytic and pentose shunt enzymes as a result of cytosolic acidification. Key problems that remain to be addressed are the production of Lonidamine under GMP conditions since Angelini Pharmaceuticals in Rome, Italy, the sole commercial source of this drug, stopped producing it in 2006. In addition, utilization of Lonidamine in the US requires IND approval by the FDA, which has previously been granted for a number of clinical trials. Finally, even though LND is a potent enhancer of the activity of a number of potent anti-cancer agents, potentially less toxic (and patentable) “targeted-tumor agents” are replacing traditional chemotherapy. Another problem remaining to be addressed is the limited solubility of Lonidamine at neutral pH. Oral delivery has led to variable results; more soluble derivatives that can be administered by the intravenous administration are needed to accurately control the dosing schedules.
CNS Activity
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL4360 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27497601 |
36.8 µM [Kd] | ||
Target ID: CHEMBL2073704 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27497601 |
36.4 µM [Kd] | ||
Target ID: CHEMBL2073663 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27497601 |
40.4 µM [Kd] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
PubMed
Title | Date | PubMed |
---|---|---|
Testin induction: the role of cyclic 3',5'-adenosine monophosphate/protein kinase A signaling in the regulation of basal and lonidamine-induced testin expression by rat sertoli cells. | 2000 Dec |
|
Recent studies on lonidamine, the lead compound of the antispermatogenic indazol-carboxylic acids. | 2002 Apr |
|
[Are mitochondria targets of anticancer drugs responsible for apoptosis?]. | 2002 Jul-Aug |
|
Hepatocytes transgenic for the full hepatitis C virus open reading frame are resistant to fas-induced cell death. | 2002 Nov |
|
Mechanism of lonidamine inhibition of the CFTR chloride channel. | 2002 Nov |
|
Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design. | 2002 Oct 15 |
|
Mitochondrial targeting drug lonidamine triggered apoptosis in doxorubicin-resistant HepG2 cells. | 2002 Oct 25 |
|
Drug specific resistance to oxaliplatin is associated with apoptosis defect in a cellular model of colon carcinoma. | 2002 Oct 9 |
|
Ultralow doses of various drugs in chemotherapy of experimental tumors. | 2003 Jan |
|
Synergistic effects of cystic fibrosis transmembrane conductance regulator and aquaporin-9 in the rat epididymis. | 2003 May |
|
The development of lonidamine for benign prostatic hyperplasia and other indications. | 2005 |
|
Mitomycin C, vinblastine and cisplatin (MVP): an active and well-tolerated salvage regimen for advanced breast cancer. | 2005 Feb 14 |
|
Pharmacologic inhibitors of PI3K/Akt potentiate the apoptotic action of the antileukemic drug arsenic trioxide via glutathione depletion and increased peroxide accumulation in myeloid leukemia cells. | 2005 May 15 |
|
Lonidamine transiently affects spermatogenesis in pubertal CD1 mice. | 2005 Oct |
|
The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. | 2006 Dec |
|
Mitomycin C and Vinorelbine for second-line chemotherapy in NSCLC--a phase II trial. | 2007 Apr 10 |
|
Lonidamine affects testicular steroid hormones in immature mice. | 2007 May 15 |
|
Evaluation of contraceptive activity of methanol extract of Dendrophthoe falcata stem in male albino rats. | 2007 May 30 |
|
[Treatment and post-treatment with lonidamine in human colon carcinoma HT-29 cell line]. | 2008 |
|
The anti-trypanosomal agent lonidamine inhibits Trypanosoma brucei hexokinase 1. | 2008 Apr |
|
Glycosyl and polyalcoholic prodrugs of lonidamine. | 2008 Apr 1 |
|
Canadian supportive care recommendations for the management of neutropenia in patients with cancer. | 2008 Jan |
|
Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. | 2009 Feb 26 |
|
Modulation of cellular radiation responses by 2-deoxy-D-glucose and other glycolytic inhibitors: implications for cancer therapy. | 2009 Sep |
|
AF-2364 is a prospective spermicide candidate. | 2010 May |
|
The fourth isoform of the adenine nucleotide translocator inhibits mitochondrial apoptosis in cancer cells. | 2010 May |
|
Adjudin-mediated Sertoli-germ cell junction disassembly affects Sertoli cell barrier function in vitro and in vivo. | 2010 Nov |
|
New scaffolds of natural origin as Integrase-LEDGF/p75 interaction inhibitors: virtual screening and activity assays. | 2013 Oct |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12814259
450 mg/day
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19001677
A malignant human glioma (U373MG) cell line was used in these studies. TMZ (temozolomide) (20, 40 or 60 microM) or LND (Lonidamine) (100, 150 or 200 microM), or the combination of both (20 and 100 microM, respectively) in 0.1 per cent dimethyl sulphoxide (DMSO) were added three days after setting up cultures, in six well plates (5 x 10(4) cells/ well). The effects of continuous treatment for two days on proliferation response and cytotoxicity were studied after trypsinization; by cell counts and the uptake of trypan blue dye (0.5%). For the study of radiation (60Co-Gamma-rays, 2 Gy) response, drugs were removed 4 h after irradiation and cultures were grown further in drug free, normal growth medium for another 20 h or 44 h.
Name | Type | Language | ||
---|---|---|---|---|
|
Official Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Code | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Brand Name | English | ||
|
Code | English | ||
|
Systematic Name | English | ||
|
Systematic Name | English |
Classification Tree | Code System | Code | ||
---|---|---|---|---|
|
NCI_THESAURUS |
C798
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
||
|
NCI_THESAURUS |
C1744
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
||
|
WHO-VATC |
QL01XX07
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
||
|
WHO-ATC |
L01XX07
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
U78804BIDR
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
CHEMBL1257030
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
39562
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
1598
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
741419
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
50264-69-2
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
100000082026
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
DTXSID5020782
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
LONIDAMINE
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
758419
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
256-510-0
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
C016371
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
m6895
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | Merck Index | ||
|
DB06266
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
4324
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
SUB08571MIG
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
50138
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY | |||
|
C1146
Created by
admin on Sat Dec 16 16:17:42 GMT 2023 , Edited by admin on Sat Dec 16 16:17:42 GMT 2023
|
PRIMARY |
ACTIVE MOIETY