Holl Ralph, Schepmann Dirk, Fröhlich Roland, Grünert Renate, Bednarski Patrick J, Wünsch Bernhard
Institut fur Pharmazeutische und Medizinische Chemie der Westfalischen Wilhelms-Universitat Munster, Munster, Germany.
J Med Chem. 2009 Apr 9;52(7):2126-37. doi: 10.1021/jm801522j.
A series of 6,8-diazabicyclo[3.2.2]nonane derivatives bearing two aromatic moieties was prepared, the affinity toward sigma(1) and sigma(2) receptors 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-5a and ent-5b served as chiral building blocks, which were derived from (S)- and (R)-glutamate, respectively. Structure-affinity relationships revealed that 11a (K(i) = 154 nM), ent-11a (K(i) = 91 nM), and ent-17a (K(i) = 104 nM) are the most potent sigma(1) ligands. High sigma(2) affinity was achieved with 17b (K(i) = 159 nM) and 8b (K(i) = 400 nM). The bicyclic sigma ligands showed a selective growth inhibition of the small cell lung cancer cell line A-427 with the benzyl ethers 11 and the benzylidene derivatives 17 being the most potent compounds. 11a has a cytotoxic potency (IC(50) = 0.92 muM), which exceeds the activity of cisplatin and interacts considerably with both sigma(1) and sigma(2) receptors.
制备了一系列带有两个芳香基团的6,8 - 二氮杂双环[3.2.2]壬烷衍生物，研究了它们对σ(1)和σ(2)受体的亲和力，并测定了对六种人类肿瘤细胞系的生长抑制作用。对映体纯的双环酮5a（(+)-(1S,5S)-6 - 烯丙基 - 8 - (4 - 甲氧基苄基)-6,8 - 二氮杂双环[3.2.2]壬烷 - 2,7,9 - 三酮）和5b（(+)-(1S,5S)-6 - 烯丙基 - 8 - (2,4 - 二甲氧基苄基)-6,8 - 二氮杂双环[3.2.2]壬烷 - 2,7,9 - 三酮）及其对映体ent - 5a和ent - 5b用作手性结构单元，它们分别衍生自(S)-和(R)-谷氨酸。结构 - 亲和力关系表明，11a（K(i) = 154 nM）、ent - 11a（K(i) = 91 nM）和ent - 17a（K(i) = 104 nM）是最有效的σ(1)配体。17b（K(i) = 159 nM）和8b（K(i) = 400 nM）具有高σ(2)亲和力。双环σ配体对小细胞肺癌细胞系A - 427表现出选择性生长抑制作用，其中苄基醚11和亚苄基衍生物17是最有效的化合物。11a具有细胞毒性效力（IC(50) = 0.92 μM），超过顺铂的活性，并且与σ(1)和σ(2)受体都有显著相互作用。
