Bickmeyer Ulf, Grube Achim, Klings Karl-Walter, Köck Matthias
Alfred-Wegener-Institut für Polar- und Meeresforschung in der Helmholtz-Gemeinschaft, Biologische Anstalt Helgoland, Kurpromenade, D-27498 Helgoland, Germany.
Toxicon. 2007 Sep 15;50(4):490-7. doi: 10.1016/j.toxicon.2007.04.015. Epub 2007 May 3.
Twelve brominated pyrrole-imidazole alkaloids from the Caribbean sponges Stylissa caribica and Agelas wiedenmayeri were tested for interactions with cellular calcium homeostasis using PC12 cells. Massadine (half maximal concentration: 5.32 +/- 0.007microM), stylissadines A (4.48 +/- 1.1microM) and B (4.6 +/- 1.6microM) as well as tetrabromostyloguanidine (15.6 +/- 0.004microM) reduced voltage-dependent calcium entry in PC12 cells as measured with Fura II as calcium indicator. Dibromopalau'amine and mauritiamine reduced voltage-dependent calcium entry but no half maximal concentration can be calculated from our results. Monomeric brominated pyrrole alkaloids such as stevensine, cyclooroidin, oxocyclostylidol, 4-bromopyrrole-2-carboxy-N(epsilon)-lysine, and 4-bromopyrrole-2-carboxyarginine showed no or only minor effects. Ageladine A itself showed fluorescence in a similar range as Fura II and therefore no data are reported here. Based on the results a structure-activity relationship could be established. Absolutely necessary for an activity seem to be a lipophilic (brominated side chain) and a hydrophilic (amino-imidazole core) substructure. The combination of these substructures may be on one hand responsible for the membrane solubility (dibromopyrrole moieties) and on the other hand for the interaction with the hydrophilic area of the calcium channel (amino-imidazole moieties) to accomplish the alkaloids neurotoxic potential.
从加勒比海绵加勒比斯氏海绵（Stylissa caribica）和维氏艾氏海绵（Agelas wiedenmayeri）中提取的12种溴化吡咯-咪唑生物碱，利用PC12细胞测试了其与细胞钙稳态的相互作用。马萨丁（半数最大浓度：5.32±0.007微摩尔）、斯氏海绵碱A（4.48±1.1微摩尔）和B（4.6±1.6微摩尔）以及四溴斯氏胍（15.6±0.004微摩尔），在用Fura II作为钙指示剂测量时，可降低PC12细胞中电压依赖性钙内流。二溴帕劳胺和毛里求斯胺可降低电压依赖性钙内流，但根据我们的结果无法计算出半数最大浓度。单体溴化吡咯生物碱，如史蒂文森碱、环奥罗因、氧环斯氏醇、4-溴吡咯-2-羧基-N（ε）-赖氨酸和4-溴吡咯-2-羧基精氨酸，未显示出作用或仅有轻微作用。阿格拉丁A本身在与Fura II相似的范围内显示荧光，因此此处未报告相关数据。基于这些结果，可以建立构效关系。活性的绝对必要条件似乎是一个亲脂性（溴化侧链）和亲水性（氨基咪唑核心）亚结构。这些亚结构的组合一方面可能负责膜溶解性（二溴吡咯部分），另一方面负责与钙通道的亲水区（氨基咪唑部分）相互作用，以实现生物碱的神经毒性潜力。
