1134584-08-9Relevant articles and documents
Dancing of the second aromatic residue around the 6,8-diazabicyclo[3.2.2] nonane framework: Influence on σ receptor affinity and cytotoxicity
Holl, Ralph,Schepmann, Dirk,Fr?hlich, Roland,Grünert, Renate,Bednarski, Patrick J.,Wünsch, Bernhard
scheme or table, p. 2126 - 2137 (2009/12/31)
A series of 6,8-diazabicyclo[3.2.2]nonane derivatives bearing two aromatic moieties was prepared, the affinity toward σ1 and σ2 receptors was investigated, and the growth inhibition of six human tumor cell lines was determined. The e
Relationships between the structure of 6-allyl-6,8-diazabicyclo[3.2.2]nonane derivatives and their σ receptor affinity and cytotoxic activity
Holl, Ralph,Schepmann, Dirk,Gruenert, Renate,Bednarski, Patrick J.,Wuensch, Bernhard
experimental part, p. 777 - 793 (2009/08/07)
A series of bridged piperazine derivatives was prepared and the affinity toward σ1 and σ2 receptors by means of radioligand binding assays as well as the inhibition of the growth of six human tumor cell lines was investigated. All possible stereoisomers of the 2-hydroxy, 2-methoxy, 2,2-dimethoxy, 2-oxo, and 2-unsubstituted 6,8-diazabicyclo[3.2.2]nonanes were prepared in a chiral pool synthesis starting with (S)- and (R)-glutamate. A Dieckmann analogous cyclization was the key step in the synthesis of the bicyclic framework. The configuration in position 2 was established by a diastereoselective LiBH4 reduction and subsequent Mitsunobu inversion. Structure-affinity relationships demonstrate that substituents in position 2 decrease σ1 receptor affinity which might be due to unfavorable interactions with the σ1 receptor protein. Without a substituent in position 2 high σ1 affinity was obtained (23a ((+)-(1S,5S)-6-allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane): Ki = 11 nM). Experiments with six human tumor cell lines showed a weak but selective growth inhibition of the human small cell lung cancer cell line A-427 by the methyl ethers ent-16b (IC50 = 18.9 μM), 21a (IC50 = 16.4 μM), ent-21a (IC50 = 20.4 μM), and 21b (IC50 = 27.1 μM) and the unsubstituted compounds 23a and 23b (42% inhibition at 20 μM).
