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首页> 外文期刊>Journal of Medicinal Chemistry >Simplified cyclic analogues of bastadin-5. Structure-activity relationships for modulation of the RyR1/FKBP12 Ca2+ channel complex
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Simplified cyclic analogues of bastadin-5. Structure-activity relationships for modulation of the RyR1/FKBP12 Ca2+ channel complex

机译：bastadin-5的简化环状类似物。调节RyR1 / FKBP12 Ca2 +通道复合物的结构活性关系

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摘要

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.
机译：Bastadin-5是海洋海绵Ianthella basta中的一种溴化大环内酰胺，可通过调节RyR1 / FKBP12复合体来增强肌肉和非肌肉细胞的肌质网（SR）内钙离子的释放。 bastadin-5的类似物为SAR研究提供了理想的靶标，以阐明bastadin-5在这些异聚通道上的结合机制和位点，这些通道介导了膜激发与Ca2 +信号级联的早期偶联中的重要步骤。以有效的SNAr大醚化为特征，由取代的苯甲醛以收敛的方式合成了简单，受环约束的bastadin-5类似物，并通过测定已知与功能性开放状态相关的[H-3] -ryanodine进行了评估Ca2 +通道。简化的14元环，阻转异构体类似物（+/-）-7，与bastadin-5一样，增强了ryanodine与RyR1 / FKBP12复合物（EC50 11μM）的结合，但是，出乎意料的是，相应的非手性18元环类似物在相同条件下，有14种有效抑制结合（IC50为6μM）。环状类似物的两个家族的结构活性关系显示出在ryanodine结合测定中的活性，其随三取代的芳基环上的Br原子被各种官能团的取代而变化。活性最高的类似物是保守二溴邻苯二酚醚部分（对应于bastadin-5结构的“西边”）的类似物。这些数据表明，basastin-5的环状类似物以复杂的方式与通道复合物相互作用，可以增强或抑制通道活性。

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