Marco-Contelles José, León Rafael, de los Ríos Cristóbal, García Antonio G, López Manuela G, Villarroya Mercedes
Laboratorio de Radicales Libres (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
Bioorg Med Chem. 2006 Dec 15;14(24):8176-85. doi: 10.1016/j.bmc.2006.09.025. Epub 2006 Sep 26.
The synthesis and the biological evaluation (neuroprotection, voltage dependent calcium channel blockade, AChE/BuChE inhibitory activity and propidium binding) of new multipotent tetracyclic tacrine analogues (5-13) are described. Compounds 7, 8 and 11 showed a significant neuroprotective effect on neuroblastoma cells subjected to Ca(2+) overload or free radical induced toxicity. These compounds are modest AChE inhibitors [the best inhibitor (11) is 50-fold less potent than tacrine], but proved to be very selective, as for most of them no BuChE inhibition was observed. In addition, the propidium displacement experiments showed that these compounds bind AChE to the peripheral anionic site (PAS) of AChE and, consequently, are potential agents that can prevent the aggregation of beta-amyloid. Overall, compound 8 is a modest and selective AChE inhibitor, but an efficient neuroprotective agent against 70mM K(+) and 60microM H(2)O(2). Based on these results, some of these molecules can be considered as lead candidates for the further development of anti-Alzheimer drugs.
本文描述了新型多效四环他克林类似物（5 - 13）的合成及其生物学评价（神经保护作用、电压依赖性钙通道阻断作用、乙酰胆碱酯酶/丁酰胆碱酯酶抑制活性以及与碘化丙啶的结合）。化合物7、8和11对遭受钙（2 +）过载或自由基诱导毒性的神经母细胞瘤细胞显示出显著的神经保护作用。这些化合物是适度的乙酰胆碱酯酶抑制剂[最佳抑制剂（11）的效力比他克林低50倍]，但被证明具有很高的选择性，因为大多数化合物未观察到丁酰胆碱酯酶抑制作用。此外，碘化丙啶置换实验表明，这些化合物与乙酰胆碱酯酶的外周阴离子位点（PAS）结合，因此是能够预防β - 淀粉样蛋白聚集的潜在药物。总体而言，化合物8是一种适度且具有选择性的乙酰胆碱酯酶抑制剂，但对70mM钾（+）和60μM过氧化氢（2）具有有效的神经保护作用。基于这些结果，其中一些分子可被视为进一步开发抗阿尔茨海默病药物的潜在候选物。
