Dancing of the second aromatic residue around the 6,8-diazabicyclo[3.2.2]nonane framework: influence on sigma receptor affinity and cytotoxicity.
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.
Holl
Ralph
R
Institut fur Pharmazeutische und Medizinische Chemie der Westfalischen Wilhelms-Universitat Munster, Munster, Germany.
Schepmann
Dirk
D
Fröhlich
Roland
R
Grünert
Renate
R
Bednarski
Patrick J
PJ
Wünsch
Bernhard
B
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism
C540188:6-allyl-2-benzylidene-8-(4-methoxybenzyl)-6,8-diazabicyclo(3.2.2)nonane; C540187:6-allyl-2-benzyloxy-8-(4-methoxybenzyl)-6,8-diazabicyclo(3.2.2)nonane; D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D017480:Receptors, sigma