Synthesis of bicyclic sigma receptor ligands with cytotoxic activity.

Abstract

All possible stereoisomeric alcohols (6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonan-2-ol) and methyl ethers (6-benzyl-2-methoxy-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane) are prepared from (R)- and (S)-glutamate. A Dieckmann analogous cyclization, which makes use of trapping the primary cyclization product with Me3SiCl, generates the bicyclic framework. Stereoselective LiBH4 reduction and Mitsunobu inversion establish the configuration in position 2. Enantiomeric alcohols 15 (1S,2S,5R) and ent-15 (1R,2R,5S) as well as diastereomeric methyl ethers ent-17 (1R,2R,5S) and ent-22 (1R,2S,5S) display high sigma1 receptor affinity. Cell growth inhibition of the stereoisomeric alcohols and methyl ethers against five human tumor cell lines is investigated. In particular, at a concentration of 20 muM the four methyl ethers stop completely the cell growth of the small cell lung cancer cell line A-427, indicating a specific target in this cell line. The IC50-values of methyl ethers ent-17 and ent-22 are in the range of the antitumor drugs cisplatin and oxaliplatin. Binding assays show that the investigated tumor cell lines express considerable amounts of sigma1 and sigma2 receptors.

• Authors: Christian Geiger, Christel Zelenka, Manuela Weigl, Roland Fröhlich, Birgit Wibbeling, Kirstin Lehmkuhl, Dirk Schepmann, Renate Grünert, Patrick J Bednarski, Bernhard Wünsch
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 24 Pg. 6144-53 (Nov 29 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17967001 (Publication Type: Journal Article)

Chemical References

• 6-benzyl-2-methoxy-8-(4-methoxybenzyl)-6,8-diazabicyclo(3.2.2)nonane
• Antineoplastic Agents
• Azabicyclo Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Receptors, sigma

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Azabicyclo Compounds (chemical synthesis, chemistry, pharmacology)
• Brain (metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Crystallography, X-Ray
• Drug Screening Assays, Antitumor
• Guinea Pigs
• Humans
• In Vitro Techniques
• Liver (metabolism)
• Molecular Structure
• Radioligand Assay
• Rats
• Receptors, sigma (agonists, antagonists & inhibitors, biosynthesis)
• Stereoisomerism
• Structure-Activity Relationship