Synthesis of Bicyclic σ Receptor Ligands with Cytotoxic Activity

Abstract

All possible stereoisomeric alcohols (6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonan-2-ol) and methyl ethers (6-benzyl-2-methoxy-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane) are prepared from (R)- and (S)-glutamate. A Dieckmann analogous cyclization, which makes use of trapping the primary cyclization product with Me3SiCl, generates the bicyclic framework. Stereoselective LiBH4 reduction and Mitsunobu inversion establish the configuration in position 2. Enantiomeric alcohols 15 (1S,2S,5R) and ent-15 (1R,2R,5S) as well as diastereomeric methyl ethers ent-17 (1R,2R,5S) and ent-22 (1R,2S,5S) display high sigma1 receptor affinity. Cell growth inhibition of the stereoisomeric alcohols and methyl ethers against five human tumor cell lines is investigated. In particular, at a concentration of 20 muM the four methyl ethers stop completely the cell growth of the small cell lung cancer cell line A-427, indicating a specific target in this cell line. The IC50-values of methyl ethers ent-17 and ent-22 are in the range of the antitumor drugs cisplatin and oxaliplatin. Binding assays show that the investigated tumor cell lines express considerable amounts of sigma1 and sigma2 receptors.

Design, synthesis and pharmacological evaluation of spirocyclic σ1 receptor ligands with exocyclic amino moiety (increased distance 1)

“…Several structural diverse r 1 ligands with high affinity are known today, including benzomorphans, conformationally constrained and flexible arylalkylamines, 33 spirocyclic compounds, 34-37 bicyclic ligands, 38,39 guanidines and steroids 20 as well as clinically used drugs like fluvoxamine 40 and haloperidol. 41 For the development of novel r 1 ligands the structural properties, which are crucial for high r 1 receptor affinity were investigated.…”

5D-QSAR for spirocyclic σ1 receptor ligands by Quasar receptor surface modeling

“…Briefly, in the competitive s 1 assay guinea pig brain membrane preparations were used as receptor material and tritium labeled (þ)-pentazocine was employed as radioligand [25,28]. For the nD-QSAR study, the compound set was divided into a training set (66 compounds, T1) and a test set (21 compounds, T2).…”

Synthesis and Pharmacological Evaluation of SNC80 Analogues with a Bridged Piperazine Ring

“…The mixture was extracted with CH 2 Cl 2 (4 ), the combined organic layers were dried (Na 2 SO 4 ), filtered, and the solvent was removed in vacuo. The residue was purified by FC (Ø = 1 cm, h = 15 cm, CH 2 Cl 2 / CH 3 OH = 9.5:0.5, V = 5 mL) to give 11 as a yellow oil (33 mg, 50 %): C 17 , 1 H, 9-H), 3.52-3.57 (m, 1 H, 1-H), 3.74-3.79 (m, 1 H, 2-H (12): Under N 2 atmosphere 11 (30 mg, 0.11 mmol) was dissolved in CH 3 CN (10 mL). Then 8 [9][10][11] (37 mg, 0.17 mmol), TBAI (4 mg, 0.011 mmol), and K 2 CO 3 (23 mg, 0.17 mmol) were added, and the mixture was heated at reflux for 16 h. After cooling to room temperature the mixture was filtered, and the solvent was removed in vacuo.…”

“…[17] Therefore, the antiproliferative effects of the prepared bicyclic compounds were investigated in a panel of six human tumor cell lines: 5637 (bladder cancer), RT-4 (bladder cancer), A-427 (small-cell lung cancer), LCLC-103H (large-cell lung cancer), DAN-G (pancreatic cancer), and MCF-7 (breast cancer). The A-427 and, to a lesser extent, MCF-7 cell lines were particularly sensitive to the antiproliferative effects of previously tested diazabicyclo[3.2.2]nonanes.…”

“…The A-427 and, to a lesser extent, MCF-7 cell lines were particularly sensitive to the antiproliferative effects of previously tested diazabicyclo[3.2.2]nonanes. [17] 247 AE 16 (n=3) In the primary screening with a test compound concentration of 20 mm the enantiomeric benzylidene derivatives 15 and ent-15 revealed the most promising cytotoxic effects. Therefore, the exact IC 50 values of both compounds were recorded.…”