Relationships between the structure of 6-substituted 6,8-diazabicyclo[3.2.2]nonan-2-ones and their sigma receptor affinity and cytotoxic activity.
A series of 2-oxo-6,8-diazabicyclo[3.2.2]nonane derivatives was prepared and the affinity towards sigma(1) and sigma(2) receptors was investigated by means of radioligand binding assays as well as their inhibition of the growth of six human tumor cell lines was studied. Starting from the enantiopure bicyclic ketones 3 and ent-3 bridged piperazines with different residues in position 6 were synthesized. The N-6 allyl protective group was removed by a RhCl(3) catalyzed double bond isomerization and subsequent hydrolysis of the resulting enamide 8. After acetalization the secondary amide 10 was alkylated and arylated. Structure affinity relationships show that a relatively large substituent, which has not necessarily to be an aromatic one, is required in position 6 for high sigma(1) receptor affinity (e.g., 12 and ent-12 with a dimethylallyl residue: K(i)=20 nM and 17 nM). Furthermore, it was shown that substituents that reduce the basicity of N-6 led to a severe decrease in sigma(1) affinity. Growth inhibition experiments with six human tumor cell lines revealed that the allyl and benzyl substituted 6,8-diazabicyclo[3.2.2]nonan-2-one derivatives 5, ent-5 and ent-14 are able to selectively inhibit the growth of the bladder cancer cell line 5637.
Holl
Ralph
R
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Münster, Germany.
Schepmann
Dirk
D
Bednarski
Patrick J
PJ
Grünert
Renate
R
Wünsch
Bernhard
B
D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006168:Guinea Pigs; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000473:Alkanes; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007659:Ketones; D017480:Receptors, sigma; C017573:nonane