Synthesis, modeling, and biological evaluation of analogues of the semisynthetic brevetoxin antagonist beta-naphthoyl-brevetoxin.
Synthesis, modeling, and biological evaluation of analogues of the semisynthetic brevetoxin antagonist beta-naphthoyl-brevetoxin.
复制标题
半合成短链藻毒素拮抗剂 β-萘酰基-短链藻毒素类似物的合成、建模和生物学评价。
DOI：
10.1002/cbic.200700317
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Baden,DanielG
中科院分区：
文献类型：
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作者：
Michelliza,Sophie;Abraham,WilliamM;Jacocks,HenryM;Schuster,Thomas;Baden,DanielG
Brevetoxins是一种由短甲藻产生的神经毒性化合物。大规模水华在人类中会导致神经毒性贝类中毒(NSP)和哮喘样症状。β-萘甲酰-短杆菌毒素是第一个半合成的短链毒素拮抗剂，已被定义为研究吸入短链毒素引起的支气管收缩机制以及所选衍生物松弛或逆转这些作用的先导化合物。为了寻找更有效的短杆菌毒素拮抗剂，人们合成了一系列β-萘甲酰-短杆菌毒素类似物。活性通过竞争置换大鼠脑突触体中的氚短毒素-3和通过绵羊的肺阻力测量来确定。此外，还进行了初步的计算结构研究。所有类似物都与大鼠脑突触体结合，亲和力类似于β-萘酰-短杆菌毒素，但在绵羊身上表现出非常不同的反应。生物学评价和计算机研究表明，大鼠脑突触体中的短链毒素结合部位可能与肺组织中的不同，空间因素和静电因素都参与了短链毒素拮抗作用的发挥。
Brevetoxins are neurotoxic compounds produced by the dinoflagellateKarenia brevis. Extensive blooms induce neurotoxic shellfish poisoning (NSP) and asthma‐like symptoms in humans. β‐naphthoyl‐brevetoxin, the first semisynthetic brevetoxin antagonist, has been defined as the lead compound in the investigation of the mechanisms of bronchoconstriction induced by inhaled brevetoxins and relaxation or reversal of those effects by selected derivatives. In pursuit of more potent and effective brevetoxin antagonists, a series of β‐naphthoyl‐brevetoxin analogues have been synthesized. Activities were determined by competitive displacement of tritiated brevetoxin‐3 from rat brain synaptosomes and by lung resistance measurements in sheep. Additionally, preliminary computational structural studies have been performed. All analogues bound to rat brain synaptosomes with affinities similar to β‐naphthoyl‐brevetoxin but exhibited very different responses in sheep. The biological evaluations along with computational studies suggest that the brevetoxin binding site in rat brain synaptosome might be different from the ones in lung tissue and both steric and electrostatic factors contribute to the efficacy of brevetoxin antagonism.