147817-50-3

Basic information

• Product Name: SIRAMESINE
• Synonyms: SIRAMESINE;1'-(4-(1-(4-fluorophenyl)-1H-indol-3-yl)butyl)-3H-spiro[isobenzofuran-1,4'-piperidine];1'-[4-[1-(4-Fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];1'-[4-[1-(4-fluorophenyl)indol-3-yl]butyl]spiro[1H-2-benzofuran-3,4'-piperidine]
• CAS NO: 147817-50-3
• Molecular Formula: C₃₀H₃₁FN₂O
• Molecular Weight: 454.586
• Mol File: 147817-50-3.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 611.4±55.0 °C(Predicted)
• Appearance: /
• Density: 1.19±0.1 g/cm3(Predicted)
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Soluble in DMSO (up to at least 25 mg/ml)
• PKA: 9.45±0.20(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: SIRAMESINE(CAS DataBase Reference)
• NIST Chemistry Reference: SIRAMESINE(147817-50-3)
• EPA Substance Registry System: SIRAMESINE(147817-50-3)

Safety Data

• Hazardous Substances Data: 147817-50-3(Hazardous Substances Data)

Usage

Description

Siramesine, also known as Lu 28-179 and 147817-50-3, is a σ2 selective agonist with potent anxiolytic and anticancer properties. It selectively targets the σ2 receptor with high affinity (IC50 of 0.2nM) and has been shown to produce non-sedating, long-lasting anxiolytic effects in rodents. Additionally, Siramesine induces caspase-independent programmed cell death in various cancer cell lines through increased levels of reactive oxygen species (ROS) and lysosomal leakage. It is also known to cause mitochondrial destabilization via loss of membrane potential and increased ROS, which contributes to its mechanism of action in triggering cell death.

Uses

Used in Anticancer Applications:
Siramesine is used as an anticancer agent for the treatment of various types of cancer, including prostate cancer. It is particularly effective in inducing programmed cell death in cancer cells through increased levels of ROS and lysosomal leakage, as well as mitochondrial destabilization.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, Siramesine is used as a selective agonist for the σ2 receptor. Its high affinity for the σ2 receptor (IC50 of 0.2nM) makes it a valuable compound for the development of new drugs targeting this receptor, with potential applications in the treatment of anxiety and cancer.
Used in Anxiety Treatment:
Siramesine is used as an anxiolytic agent for the treatment of anxiety disorders. Its non-sedating and long-lasting effects make it a promising candidate for the development of new anxiety medications.
Brand Name:
Provenge (Dendreon) is a brand name associated with Siramesine, indicating its use in the treatment of prostate cancer.

References

1) Perregaard?et al.?(1995),?Sigma ligands with subnanomolar affinity and preference for the sigma 2 binding site. 1. 3-(omega-aminoalkyl)-1H-indoles; J. Med. Chem.?38?1998 2) Sanchez?et al.?(1997),?The selective sigma2-ligand Lu 280179 has potent anxiolytic effects in rodents; J. Pharmacol. Exp. Ther.?283?1323 3) Ostenfeld?et al.?(2005),?Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress;?Cancer Res.?65?8975 4) Ostenfeld et al. (2008),?Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation; Autophagy?4?487 5) Dielschneider?et al.?(2016),?Lysosomotropic agents selectively target chronic lymphocytic leukemia cells due to altered sphingolipid metabolism; Leukemia?30?1290 6) Cesen?et al.?(2013),?Siramesine triggers cell death through destabilization of mitochondria, but not lysosomes; Cell Death Dis.?4?e818

Upstream product

• 38309-60-3 3H-spiro[2-benzofuran-1,4'-piperidine] 
• 163630-97-5 4-<1-(4-fluorophenyl)-1H-indol-3-yl>-1-butanol methanesulfonate ester 
• 133-32-4 4-indol-3-yl-butyric acid 
• 15591-70-5 methyl 4-(1H-indol-3-yl)butanoate 
• 352-34-1 4-fluoro-1-iodobenzene 
• 147372-95-0 4-<1-(4-fluorophenyl)-1H-indol-3-yl>-1-butanol 
• 3364-37-2 4-(1H-indol-3-yl)butan-1-ol 

Relevant articles and documents

Novel indole-based sigma-2 receptor ligands: synthesis, structure-affinity relationship and antiproliferative activity

We report the synthesis and biological evaluation of a series of indole-based σ2 receptor ligands derived from siramesine. In vitro competition binding assays showed that these analogues possessed high to moderate affinity and selectivity for σ2 receptors. Structure-affinity relationship analyses of these indole-based σ2 receptor ligands were performed. In the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 1a and 1b displayed significant and comparable antiproliferative activity in DU145, MCF7 and C6 cells to siramesine. In cell cycle analyses, compounds 1a, 1b and siramesine were found to induce a G1 phase cell cycle arrest in DU145 cells using flow cytometry. The combination of 5,6-dimethoxyisoindoline scaffold and N-(4-fluorophenyl)indole moiety was identified as a new σ2 receptor ligand deserving further investigation as an antitumor agent.

1'-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine] hydrohalogenides

The present invention relates to a hydrohalogenide of 1′-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H),4′-piperidine], pharmaceutical compositions containing the acid addition salts and the use thereof for the treatment of psychic and neurological disorders.

σ Ligands with subnanomolar affinity and preference for the σ2 binding site. 1. 3-(ω-Aminoalkyl)-1H-indoles

A series of 4-(1H-indol-3-yl)-1-butyl-substituted 4-phenylpiperidines, 4- phenyl-1,2,3,6-terrahydropyridines, and 4-phenylpiperazines was synthesized. The phenyl group was optionally substituted with 4-fluoro or 2-methoxy substituents. High affinity for both σ1 and σ1 binding sites was achieved with these compounds. Additionally, these compounds had relatively high affinity for serotonin 5-HT(1A) and 5-HT(2A), dopamine D2, and adrenergic α1 receptors. Introduction of a 4-fluorophenyl substituent at the indole nitrogen atom rendered very selective σ2 ligands with subnanomolar affinity for the σ2 binding site. The prototype of such a compound was 1-(4- fluorophenyl)-3-[4-[4-(4-fluorophenyl)-1-piperidinyl]-1-butyl]-1H-indole, 11a (code no. Lu 29-253). This compound had the following binding affinities: IC50 (σ1) = 16 nM, IC50 (σ2) = 0.27 riM, IC50 (5-HT(1A)) = 22 000 nM, IC50 (5-HT(2A)) = 270 nM, IC50 (D2) = 4200 nM, IC50 (α1) = 220nM. Spiro-joining of the phenyl and the piperidine rings into a spiro[isobenzofuran-1(3H),4'-piperidinel ring system resulted in even more selective compounds. Variations of the 1-substituent at the indole and of the chain length of the alkylene spacer group were studied. The optimal compound was the spiro analogue of compound 11a. This compound is 1'-14-[1(4- fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4'- piperidine], 14f (code no. Lu 28-179), with the binding affinities: IC50 (σ1) = 17 nM, IC50 (σ2) = 0.12 nM, IC50 (5-HT(1A)) = 21 000 nM, IC50 (5-HT(2A)) = 2000 nM, IC50 (D2) = 800 nM, IC50 (α1) = 330 nM. However, the most selective σ2 versus σ1 ligand was the tropane derivative 1-(4-fluorophenyl)-3-[4-[3-(4-fluorophenyl)-8- azabicyclo[3.2.1]oct-2-en-8-yl]-1-butyl]-1H-indole, 15a. This compound had the following binding affinities: IC50 (σ1) = 1200 nM, IC50 (σ2) = 2.5 nM. Potent anxiolytic activity in the black/white box exploration test in rats was found with the two most prominent σ2 ligands Lu 29-253 and Lu 28- 179. Good penetration into the CNS was documented both after subcutaneous and peroral administration of Lu 28-179 by ex vivo binding studies. Long duration of action was demonstrated both in ex vivo binding (T(1/2) ~ 20 h) and in the black/white box exploration test.