Relationships between the structure of 6-allyl-6,8-diazabicyclo[3.2.2]nonane derivatives and their sigma receptor affinity and cytotoxic activity.
A series of bridged piperazine derivatives was prepared and the affinity toward sigma(1) and sigma(2) 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 LiBH(4) reduction and subsequent Mitsunobu inversion. Structure-affinity relationships demonstrate that substituents in position 2 decrease sigma(1) receptor affinity which might be due to unfavorable interactions with the sigma(1) receptor protein. Without a substituent in position 2 high sigma(1) affinity was obtained (23a ((+)-(1S,5S)-6-allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane): K(i)=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 (IC(50)=18.9 microM), 21a (IC(50)=16.4 microM), ent-21a (IC(50)=20.4 microM), and 21b (IC(50)=27.1 microM) and the unsubstituted compounds 23a and 23b (42% inhibition at 20 microM).
Holl
Ralph
R
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Schepmann
Dirk
D
Grünert
Renate
R
Bednarski
Patrick J
PJ
Wünsch
Bernhard
B
D000473:Alkanes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003500:Cyclization; D006801:Humans; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017480:Receptors, sigma / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000473:Alkanes; D000970:Antineoplastic Agents; D010879:Piperazines; D017480:Receptors, sigma; C017573:nonane