Simplified cyclic analogues of bastadin-5.: Structure-activity relationships for modulation of the RyR1/FKBP12 Ca2+ channel complex
Simplified cyclic analogues of bastadin-5.: Structure-activity relationships for modulation of the RyR1/FKBP12 Ca2+ channel complex
复制标题
DOI：
10.1021/jm050708u
复制
发表时间：
2006-07-27
影响因子：
7.3
通讯作者：
Molinski, Tadeusz F.
中科院分区：
文献类型：
--
作者：
Masuno, Makoto N.;Pessah, Isaac N.;Molinski, Tadeusz F.
Bastadin-5是一种来自海绵Ianthella basta的溴化大分子双内酰胺，通过调节RyR 1/FKBP 12复合物增强肌肉和非肌肉细胞肌浆网（SR）内钙库的释放。巴斯塔丁-5的类似物提出了理想的SAR研究的目标，以阐明这些异聚体通道上的门控机制和巴斯塔丁-5结合位点，这些异聚体通道介导膜兴奋与Ca 2+信号级联的早期偶联中的重要步骤。简单的，环约束的类似物bastadin-5的合成取代苯甲醛在收敛的方式，具有有效的SNAr macroetherification，并在测定中进行评估，测量[H-3]-ryanodine，这是已知的相关功能开放状态的钙离子通道。简化的14元环，阻转异构体类似物（+/-）-7，如巴斯塔丁-5，增强ryanodine与RyR 1/FKBP 12复合物的结合（EC 50 11 μ M），然而，出乎意料的是，相应的非手性18元环类似物14在相同条件下有效抑制结合（IC 50 6 μ M）。两个家庭的环状类似物的结构-活性关系表明，在兰尼碱结合试验，不同的三取代的芳基环上的Br原子的各种官能团的取代的活性。最具活性的类似物是那些保留二溴邻苯二酚醚部分的类似物，该部分对应于巴斯塔丁-5结构的“西边缘”。这些数据表明，bastadin-5的环状类似物与通道复合物以复杂的方式相互作用，可以增强或抑制通道活性。
Bastadin-5, a brominated macro-dilactam from the marine sponge Ianthella basta, enhances release of Ca2+ from stores within the sarcoplasmic reticulum (SR) of muscle and nonmuscle cells by modulating RyR1/FKBP12 complex. Analogues of bastadin-5 present desirable targets for SAR studies to shed light on the gating mechanism and locus of bastadin-5 binding on these heteromeric channels that mediate essential steps in early coupling of membrane excitation to Ca2+ signaling cascades. Simple, ring-constrained analogues of bastadin-5 were synthesized from substituted benzaldehydes in a convergent manner, featuring an efficient SNAr macroetherification, and evaluated in an assay that measures [H-3]-ryanodine that is known to correlate with the functional open state of the Ca2+ channel. The simplified 14-membered ring, atropisomeric analogue (+/-)-7, like bastadin-5, enhanced ryanodine binding to the RyR1/FKBP12 complex (EC50 11 mu M), however, unexpectedly, the corresponding achiral 18-membered ring analogue 14 potently inhibited binding (IC50 6 mu M) under the same conditions. Structure-activity relationships of both families of cyclic analogues showed activity in a ryanodine binding assay that varied with substitutions of the Br atom on the trisubstituted aryl ring by various functional groups. The most active analogues were those that conserved the dibromocatechol ether moiety that corresponds to the 'western edge' of the bastadin-5 structure. These data suggest that cyclic analogues of bastadin-5 interact with the channel complex in a complex manner that can either enhance or inhibit channel activity.