Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstraße 58-62, D-48149, Münster, Germany.
Org Biomol Chem. 2010 Dec 21;8(24):5525-40. doi: 10.1039/c0ob00402b. Epub 2010 Oct 15.
The key step in the synthesis of the 7,9-diazabicyclo[4.2.2]decane system was a modified Dieckmann condensation of piperazinebutyrate 11, which makes use of trapping the first cyclized intermediate with TMS-Cl. Reduction of the bicyclic ketone 14 with LiBH(4) at -90 °C provided diastereoselectively (>99 : 1) the syn-configured alcohol 15a, which was converted into the final alcohol and ethers 16a-g. The configuration at the 2-position was established by X-ray structure analysis of methyl and ethyl ethers 15b and 15c. In contrast to bicyclic systems with a three-carbon bridge, inversion of the configuration at the 2-position of the alcohol 15a failed to give the inverted alcohol 19a. However, an unselective reduction of the ketone 24 with L-Selectride led to the diastereomeric alcohols 16a and 25a in the ratio 36 : 64. LiAlH(4) reduction of the tosylate 20 and the alkene 18 yielded the diazabicyclo-decane 26 and -decene 27 without further substituents at the four-carbon bridge. The σ(1) and σ(2) receptor affinities were investigated in receptor binding studies with radioligands. All test compounds showed a lower σ(1) affinity than the corresponding bicyclic derivatives with a three-membered bridge. The reduced σ(1) receptor affinity is attributed to the larger four-membered bridge. This hypothesis is supported by the alkene 27, which represents the most potent σ(1) ligand of this series (K(i) = 7.5 nM). In the alkene 27 the size and flexibility of the bridge is considerably reduced by the double bond. The methyl ether 25b and the unsubstituted derivatives 26 and 27 revealed moderate inhibition of the growth of the human tumor cell lines A-427, 5637 and MCF-7. Again, these compounds are less potent than the analogues with a three-membered bridge. The IC(50)-value of the most potent σ(1) ligand 27 against the small cell lung cancer cell line A-427 (IC(50) = 10 μM) should be emphasized, since this cell line is particularly sensitive to homologues with a three-carbon bridge.
7,9-二氮杂双环[4.2.2]癸烷系统的合成关键步骤是利用 TMS-Cl 捕获第一个环化中间体，对哌嗪丁酸 11 进行改良的狄克曼缩合反应。在-90°C 下用 LiBH(4)还原双环酮 14 可选择性地 (>99 : 1)提供顺式构型的醇 15a，后者可转化为最终的醇和醚 16a-g。通过对甲酯和乙酯 15b 和 15c 的 X 射线结构分析确定了 2 位的构型。与具有三碳桥的双环系统相比，2 位醇 15a 的构型翻转未能得到反式醇 19a。然而，用 L-Selectride 对酮 24 进行非选择性还原导致非对映异构体醇 16a 和 25a 的比例为 36 : 64。用 LiAlH(4)还原 tosylate 20 和烯烃 18 得到无进一步取代的二氮杂双环癸烷 26 和 -癸烯 27。在受体结合研究中用放射性配体进行σ(1)和σ(2)受体亲和力研究。所有测试化合物的σ(1)亲和力均低于具有三碳桥的相应双环衍生物。较低的 σ(1)受体亲和力归因于较大的四碳桥。这一假设得到了烯烃 27 的支持，它是该系列中最有效的 σ(1)配体(K(i) = 7.5 nM)。在烯烃 27 中，双键大大降低了桥的尺寸和灵活性。甲基醚 25b 和未取代的衍生物 26 和 27 对人肿瘤细胞系 A-427、5637 和 MCF-7 的生长有适度的抑制作用。同样，这些化合物的效力低于具有三碳桥的类似物。应该强调的是，最有效的 σ(1)配体 27 对小细胞肺癌细胞系 A-427 的 IC(50)值(IC(50) = 10 μM)，因为该细胞系对具有三碳桥的同系物特别敏感。
