50264-69-2

Basic information

• Product Name: Lonidamine
• Synonyms: af1890;dica;doridamina;DICLONDAZOLIC ACID;LONIDAMINE;1-[2,4-DICHLOROBENZYL]-1H-INDAZOLE-3-CARBOXYLIC ACID;1-[(2,4-DICHLOROPHENYL)METHYL]-1H-INDAZOLE-3-CARBOXYLIC ACID;1-(2,4-Dichlorobenzyl)indazole-3-carboxylic acid
• CAS NO: 50264-69-2
• Molecular Formula: C₁₅H₁₀Cl₂N₂O₂
• Molecular Weight: 321.16
• EINECS: 256-510-0
• Product Categories: API;DORIDAMINA;inhibitor;Anti-cancer&immunity
• Mol File: 50264-69-2.mol

Chemical Properties

• Melting Point: 207-209°C
• Boiling Point: 537.9 °C at 760 mmHg
• Flash Point: 280.6 °C
• Appearance: white to light yellow crystal
• Density: 1.4835 (rough estimate)
• Vapor Pressure: 2.11E-12mmHg at 25°C
• Refractive Index: 1.6070 (estimate)
• Storage Temp.: Store at RT
• Solubility: Soluble in DMSO (up to 25 mg/ml).
• PKA: 3.00±0.10(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.
• CAS DataBase Reference: Lonidamine(CAS DataBase Reference)
• NIST Chemistry Reference: Lonidamine(50264-69-2)
• EPA Substance Registry System: Lonidamine(50264-69-2)

Safety Data

• Hazard Codes: T
• Statements: 60-22-40
• Safety Statements: 53-22-36/37/39-45
• WGK Germany: 3
• RTECS: NK7886000
• Hazardous Substances Data: 50264-69-2(Hazardous Substances Data)

Usage

Uses

Used in Anticancer Applications:
Lonidamine is used as an antineoplastic agent for the treatment of various cancers, including lung, breast, prostate, and brain tumors. Its clinical effect is associated with changes in cellular energy metabolism, specifically by inhibiting glycolysis in cancer cells and enhancing aerobic glycolysis in normal cells.
Used in Contraceptive Applications:
Lonidamine is used as a contraceptive agent, potentially due to its ability to inhibit glycolysis, which may affect sperm cell energy production and function.
Used in Spermicidal Applications:
Lonidamine is used as a spermicidal agent, likely because of its inhibitory effect on glycolysis, which could disrupt sperm cell energy metabolism and reduce their viability.

References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1477623/ https://en.wikipedia.org/wiki/Lonidamine

References

1) Gatto?et al. (2002),?Recent studies on lonidamine, the lead compound of the antispermatogenic indazol-carboxylic acids; Contraception,?65?277 2) Floridi?et al., (1981),?Effect of Lonidamine on the Energy Metabolism of Ehrlich Ascites Tumor Cells; Cancer Res.,?41?4661 3) Ravagnan?et al. (1999),?Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore; Oncogene,?18?2537 4) Ben-Horin?et al. (1995),?Mechanism of Action of the Antineoplastic Drug Lonidamine: 31P and 13C Nuclear Magnetic Resonance Studies; Cancer Res.?55?2814 5) Nath?et al. (2016),?Mechanism of antineoplastic activity of lonidamine; Biochim.Biophys.Acta Reviews on Cancer?1866?151

Originator

Angelini (Italy)

Biological Activity

Anticancer and antispermatogenic agent in vitro and in vivo . Inhibits cellular energy metabolism in some cells via inhibition of mitochondrial hexokinase. Also blocks CFTR Cl - channels in vitro .

Biochem/physiol Actions

Inhibits the energy metabolism of neoplastic cells by interfering with hexokinase and disrupting uncoupler-stimulated mitochondrial electron transport; damages cell and mitochondrial membranes.

InChI:InChI=1/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)

Upstream product

• 43120-28-1 methyl 1H-indazole-3-carboxylate 
• 4498-67-3 1H-Indazole-3-carboxylic acid 
• 94-99-5 2,4-Dichlorobenzyl chloride 
• 920019-58-5 (1-(2,4-dichlorobenzyl)-1H-indazol-3-yl)methanol 
• 64132-13-4 3-(hydroxymethyl)-1H-indazole 
• 99233-20-2 α-hydroxy-2-bromoacetophenone 
• 2142-69-0 2-bromophenyl methyl ketone 
• 252025-50-6 methyl 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylate 
• 20443-99-6 2,4-dichlorobenzyl bromide 

Downstream Products

• 875577-70-1 C₂₄H₂₂Cl₂N₂O₈ 
• 252025-50-6 methyl 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylate 
• 50264-84-1 ethyl lonidamine 
• 874110-84-6 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic chloride 

Relevant articles and documents

Multiaction Platinum(IV) Prodrug Containing Thymidylate Synthase Inhibitor and Metabolic Modifier against Triple-Negative Breast Cancer

Multifunctional platinumIV anticancer prodrugs have the potential to enrich the anticancer properties and overcome the clinical problems of drug resistance and side effects of platinumII anticancer agents. Herein, we develop dual and triple action platinumIV complexes with targeted and biological active functionalities. One complex (PFL) that consists of cisplatin, tegafur, and lonidamine exhibits strong cytotoxicity against triple negative breast cancer (TNBC) cells. Cellular uptake and distribution studies reveal that PFL mainly accumulates in mitochondria. As a result, PFL disrupts the mitochondrial ultrastructure and induces significant alterations in the mitochondrial membrane potential, which further leads to an increase in production of reactive oxygen species (ROS) and a decrease in ATP synthesis in MDA-MB-231 TNBCs. Western blot analysis reveals the formation of ternary complex of thymidylate synthase, which shows the intracellular conversion of tegafur into 5-FU after its release from PFL. Furthermore, treatment with PFL impairs the mitochondrial function, leading to the inhibition of glycolysis and mitochondrial respiration and induction of apoptosis through the mitochondrial pathway. The RNA-sequencing experiment shows that PFL can perturb the pathways involved in DNA synthesis, DNA damage, metabolism, and transcriptional activity. These findings demonstrate that PFL intervenes in several cellular processes including DNA damage, thymidylate synthase inhibition, and perturbation of the mitochondrial bioenergetics to kill the cancer cells. The results highlight the significance of a triple-action prodrug for efficient anticancer therapy for TNBCs.

MODULATORS OF MAS-RELATED G-PROTEIN RECEPTOR X4 AND RELATED PRODUCTS AND METHODS

Methods are provided for modulating MRGPR X4 generally, or for treating a MRGPR X4-dependent condition more specifically, by contacting MRGPR X4 or administering to a subject in need thereof, respectively, an effective amount of a compound having structure (I): or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein E, Q, W, Z, R1, R2, R3, and R4 are as defined herein. Pharmaceutical compositions containing such compounds, as well as compounds themselves, are also provided.

Preparation methods of 1H-indazol-3-carboxylic acid derivative, granisetron and lonidamine

The invention relates to preparation methods of a 1H-indazol-3-carboxylic acid derivative, granisetron and lonidamine. The 1H-indazol-3-carboxylic acid derivative is a compound with a structure shown in a formula (1) and a formula (2), and is mainly structurally characterized by having a 1H-indazol-3-carboxylic acid amide skeleton and a 1H-indazol-3-carboxylic ester skeleton. The 1H-indazol-3-carboxylic acid derivative can be synthesized by taking simple o-aminophenylacetic acid amide or o-aminophenylacetic acid ester as an initial raw material. The 1H-indazol-3-carboxylic acid derivative is a key intermediate for synthesizing a plurality of medicines, such as granisetron, lonidamine and the like. The synthesis method of the 1H-indazol-3-carboxylic acid derivative and the drug molecules glassetron and lonidamine is simple, the reaction condition is mild, the reaction speed is high, the yield is high, and purification is easy.

Lysosomal-targeted anticancer half-sandwich iridium(III) complexes modified with lonidamine amide derivatives

Ten half-sandwich iridium complexes containing lonidamine amide derivatives were synthesized and characterized. Unlike lonidamine, which acts on mitochondria, its iridium complexes successfully targeted lysosomes and induced lysosomal damage. Antiproliferation studies showed that most of the complexes have higher anticancer activity against A549 and HeLa cells than cisplatin. The antitumor activity of complex 6 is 2.69 times that of cisplatin against A549 cells. We also performed antitumor tests on ligands L1 and L5, and proved that they exhibit excellent antitumor activity only after binding to the metal center. The bovine serum albumin (BSA) binding test showed that the complexes had the ability to bind to BSA, and they interact with BSA by a static mechanism. The complexes can also cause changes in mitochondrial membrane potential and can produce active oxygen species better than active control. NADH/NAD+ transformation experiments were used to determine if the production of ROS was caused by the transformation of NADH/NAD+. We also explored the way that the complexes enter cells.

Structure-activity relationship study and discovery of indazole 3-carboxamides as calcium-release activated calcium channel blockers

Aberrant activation of mast cells contributes to the development of numerous diseases including cancer, autoimmune disorders, as well as diabetes and its complications. The influx of extracellular calcium via the highly calcium selective calcium-release activated calcium (CRAC) channel controls mast cell functions. Intracellular calcium homeostasis in mast cells can be maintained via the modulation of the CRAC channel, representing a critical point for therapeutic interventions. We describe the structure-activity relationship study (SAR) of indazole-3-carboxamides as potent CRAC channel blockers and their ability to stabilize mast cells. Our SAR results show that the unique regiochemistry of the amide linker is critical for the inhibition of calcium influx, the release of the pro-inflammatory mediators β-hexosaminidase and tumor necrosis factor α by activated mast cells. Thus, the indazole-3-carboxamide 12d actively inhibits calcium influx and stabilizes mast cells with sub-μM IC50. In contrast, its reverse amide isomer 9c is inactive in the calcium influx assay even at 100?μM concentration. This requirement of the specific 3-carboxamide regiochemistry in indazoles is unprecedented in known CRAC channel blockers. The new structural scaffolds described in this report expand the structural diversity of the CRAC channel blockers and may lead to the discovery of novel immune modulators for the treatment of human diseases.

Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII

A series of sulfocoumarin-, coumarin-, and 4-sulfamoylphenyl-bearing indazole-3-carboxamide hybrids were synthesized and investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Compounds 6 a–g (amide derivatives) and 7 a–h (triazoles) act as “prodrugs”, and their hydrolysis products are the de facto CA inhibitors. These compounds displayed sub-micromolar to high-nanomolar inhibitory activity against hCA isoforms IX and XII, which were recently validated as antitumor drug targets. Moreover, no inhibition of the off-target hCA I and II isoforms was observed. Compounds 8 a–f (another set of triazoles) exhibited nanomolar inhibition against hCA isoforms I, II, IX and XII, among which compounds 8 c, 8 d, and 8 f were found to inhibit the tumor-associated hypoxia-induced hCA isoform IX with Ki values of 1.8, 2.3, and 2.0 nm respectively. Further exploration of these compounds could be useful for the development of novel antitumor agents with selective mechanisms of CA inhibitory action.

Preparation method of indazole and application of indazole in medicine synthesis

The invention belongs to the field of chemicals, and relates to a preparation method of indazole and an application of the indazole in medicine synthesis. The invention discloses a preparation method of indazole and an application of the indazole in synthesizing 1H-indazole-3-carboxylic acid, lonidamine, a compound 8, a compound 9, a compound 10, axitinib, YD-3, YC-1 and similar substances thereof.

Copper(I) Oxide-Mediated Cyclization of o-Haloaryl N-Tosylhydrazones: Efficient Synthesis of Indazoles

An efficient synthesis of indazoles from readily accessible E/Z mixtures of o-haloaryl N-tosylhydrazones has been developed. The thermo-induced isomerization of N-tosylhydrazones is discussed. A series of valuable indazole derivatives are prepared in good yields, and the method has been successfully applied to the synthesis of the bioactive compounds, lonidamine, AF-2785, axitinib, YC-1 and YD-3.

METHOD FOR SYNTHESIS OF LONIDAMINE AND RELATED INDAZOLE DERIVATIVES

Methods are provided for making highly pure preparations of lonidamine and related indazole derivatives.

Medicines for treating tumoral pathologies containing the ro5-4864 compound and an apoptosis-inducing agent

The invention concerns the use of Ro5-4864, and compounds derived therefrom, for preparing medicines for treating tumoral pathologies. The invention also concerns said compounds combined with an apoptosis-inducing agent, as combination products for simultaneous, separate or prolonged use, in cancer therapy.