Synthesis of Bicyclic Receptor Ligands with Cytotoxic Activity

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• 作者：Christian Geiger ; Christel Zelenka ; Manuela Weigl ; Roland Fr&ouml ; hlich ; Birgit Wibbeling ; Kirstin Lehmkuhl ; Dirk Schepmann ; Renate Grü ; nert ; Patrick J. Bednarski ; Bernhard Wü ; nsch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：6144 - 6153
• 全文大小：158K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

All possible stereoisomeric alcohols (6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonan-2-ol) andmethyl 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 primarycyclization product with Me₃SiCl, generates the bicyclic framework. Stereoselective LiBH₄ reduction andMitsunobu inversion establish the configuration in position 2. Enantiomeric alcohols 15 (1S,2S,5R) andent-15 (1R,2R,5S) as well as diastereomeric methyl ethers ent-17 (1R,2R,5S) and ent-22 (1R,2S,5S) displayhigh ₁ receptor affinity. Cell growth inhibition of the stereoisomeric alcohols and methyl ethers againstfive human tumor cell lines is investigated. In particular, at a concentration of 20 M the four methyl ethersstop completely the cell growth of the small cell lung cancer cell line A-427, indicating a specific target inthis cell line. The IC₅₀-values of methyl ethers ent-17 and ent-22 are in the range of the antitumor drugscisplatin and oxaliplatin. Binding assays show that the investigated tumor cell lines express considerableamounts of ₁ and ₂ receptors.