| مستخلص: |
A series of 6,8-diazabicyclo[3.2.2]nonane derivatives bearing two aromatic moieties was prepared, the affinity toward σ1and σ2receptors was investigated, and the growth inhibition of six human tumor cell lines was determined. The enantiopure bicyclic ketones 5a((+)-(1S,5S)-6-allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane-2,7,9-trione) and 5b((+)-(1S,5S)-6-allyl-8-(2,4-dimethoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane-2,7,9-trione) as well as their enantiomers ent-5aand ent-5bserved as chiral building blocks, which were derived from (S)- and (R)-glutamate, respectively. Structure−affinity relationships revealed that 11a(Ki= 154 nM), ent-11a(Ki= 91 nM), and ent-17a(Ki= 104 nM) are the most potent σ1ligands. High σ2affinity was achieved with 17b(Ki= 159 nM) and 8b(Ki= 400 nM). The bicyclic σ ligands showed a selective growth inhibition of the small cell lung cancer cell line A-427 with the benzyl ethers 11and the benzylidene derivatives 17being the most potent compounds. 11ahas a cytotoxic potency (IC50= 0.92 μM), which exceeds the activity of cisplatin and interacts considerably with both σ1and σ2receptors. [ABSTRACT FROM AUTHOR] |
