Masuno Makoto N, Pessah Isaac N, Olmstead Marilyn M, Molinski Tadeusz F
Department of Chemistry and Biochemistry, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
J Med Chem. 2006 Jul 27;49(15):4497-511. doi: 10.1021/jm050708u.
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 S(N)Ar macroetherification, and evaluated in an assay that measures [3H]-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 microM), however, unexpectedly, the corresponding achiral 18-membered ring analogue 14 potently inhibited binding (IC50 6 microM) 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.
巴斯他汀-5是一种从海洋海绵Ianthella basta中提取的溴化大环二内酰胺，它通过调节兰尼碱受体1（RyR1）/FK506结合蛋白12（FKBP12）复合物，增强肌肉和非肌肉细胞肌浆网（SR）内储存的Ca2+释放。巴斯他汀-5的类似物为SAR研究提供了理想的靶点，以阐明巴斯他汀-5在这些异源通道上的门控机制和结合位点，这些通道介导了膜兴奋与Ca2+信号级联早期偶联的关键步骤。以收敛的方式由取代苯甲醛合成了简单的、环受限的巴斯他汀-5类似物，其具有高效的亲核芳香取代大环醚化反应，并在一种测量[3H]-ryanodine的试验中进行了评估，已知该试验与Ca2+通道的功能开放状态相关。简化的14元环、阻转异构类似物（±）-7与巴斯他汀-5一样，增强了ryanodine与RyR1/FKBP12复合物的结合（EC50为11 microM），然而，出乎意料的是，相应的非手性18元环类似物14在相同条件下强烈抑制结合（IC5o为6 microM）。这两类环状类似物的构效关系表明，在ryanodine结合试验中，活性随三取代芳基环上Br原子被各种官能团取代而变化。活性最高的类似物是那些保留了与巴斯他汀-5结构“西边缘”相对应的二溴儿茶酚醚部分的类似物。这些数据表明，巴斯他汀-5的环状类似物以复杂的方式与通道复合物相互作用，既可以增强也可以抑制通道活性。
