FLUORO ANALOGS OF LY333531, LY317644, AND STAUROSPORINE

描述：氟标记的抑制剂类似物的合成 拟定将LY 333531、LY 317644和星形孢菌素用作氟-NMR 蛋白激酶C（PKC）探针。 LY 333531为14元环 大环双吲哚基马来酰亚胺（MBIM），其对 PKC β亚型。 LY 333531最近被证明可以正常化 PKC-β II活性和改善体内糖尿病并发症。 LY 317644是十五元环大环双吲哚基马来酰亚胺， 对PKC的选择性高于钙钙调蛋白依赖性蛋白激酶。 星形孢菌素是一种吲哚并咔唑生物碱，具有有趣的吡喃糖 双-N-糖苷环系统。 星形孢菌素是一种强效但无选择性的 蛋白激酶抑制剂已广泛用于生物化学领域， 问题研究 这些化合物被制备成NMR探针，作为长期研究的一部分。 合作项目，以确定结构基础， LY 333531对PKC的ATP竞争性、亚型选择性抑制。 选择 具有一系列结构元素和选择性特征的抑制剂将 提供最好的机会，以检测共同的和独特的功能， PKC异构体的催化结构域。 这些柔性的构造 化合物，同时结合到PKC的每种亚型，如从差异 在双异构氟化物类似物与 构效关系，或直接从实验研究 蛋白质抑制剂复合物，将提供深入了解的几何形状， 结合位点 MBIM的合成基于PI中开发的通用路线 laboratories. 星形孢菌素类似物的合成是基于 原始的合成方法，有可能解决感兴趣的 吲哚并咔唑生物碱合成中的问题，特别是 关于内酰胺区域化学和双-N-糖苷 立体化学 针对几种PKC同种型的生物活性将 确定每种化合物的含量。 核磁共振溶液构象研究 将进行5 '-氟星形孢菌素的非对映异构体的测定，以确定 相应的邻位F19-H1和F19-C13耦合常数的大小 椅子和船的构象，并确定的影响， 氟对溶液构象的影响。

DESCRIPTION: The synthesis of fluorine-labeled analogs of the inhibitors LY333531, LY317644, and staurosporine are proposed for use as fluorine-NMR probes for protein kinase C (PKC). LY333531 is a 14-membered ring macrocyclic bisindolylmaleimide (MBIM) that is highly selective for the beta-isoform of PKC. LY333531 has recently been shown to normalize PKC-betaII activity and to ameliorate diabetic complications in vivo. LY317644 is a fifteen-membered ring macrocyclic biindolylmaleimide that is very selective for PKC over calcium calmodulin-dependent protein kinase. Staurosporine is an indolocarbazole alkaloid with an interesting pyranose bis-N-glycoside ring system. Staurosporine is a potent but unselective protein kinase inhibitor that has seen widespread use in biochemical studies. These compounds are being prepared as NMR probes as part of a long term collaborative project to determine the structural basis for the ATP-competitive, isoform-selective inhibition of PKC by LY333531. Selecting inhibitors with a range of structural elements and selectivity profiles will provide the best opportunity to detect common and unique features of the catalytic domains of PKC isoforms. The conformation of these flexible compounds while bound to each isoform of PKC, as determined from differences in the activity of diasteriomeric fluoride analogs in conjunction with structure-activity relationships, or directly from experimental studies on protein-inhibitor complexes, will provide insight into the geometry of the binding site. The synthesis of the MBIM are based on a common route developed in the PI's laboratories. The synthesis of the staurosporine analogs are based on an original synthetic approach which has the potential to address interesting issues in the synthesis of indolocarbazole alkaloids, in particular with respect to the lactam regiochemistry and the bis-N-glycoside stereochemistry. The biological activity against several PKC isoforms will be determined for each compound. An NMR solution conformation study of both diastereomers of 5'-fluorostaurosporine will be performed to determine the magnitude of the vicinal F19-H1 and F19-C13 coupling constants corresponding to the chair and boat conformers, and to determine the effect of the fluorine on the solution conformation.