Diacylglycerol Lactones as C1 Ligands for Protein Kinase C and Related Proteins

我们发现，通过固相方法产生的DAG-内酯文库产生了一个 许多独特的生物活动。两个物种化学多样性的细微差异 这些区域的结合产生了我们所说的化学拉链 编码，能够将一个相对较小的化学空间转化为一个更大的宇宙， 生物活性，因为细胞内含有膜的细胞器似乎能够 破解这些化学品的邮政编码据推测，与蛋白激酶C（PKC）结合后， 同工酶或其它非激酶靶蛋白， 膜相互作用的C1结构域，所产生的复合物是针对不同的细胞内 访问不同衬底的位置。多项细胞生物测定显示， 结合PKC-α的DAG-内酯将其生物学库扩展为更大的 结构域，引发不同的细胞应答（J. Med. Chem. 2008，51，5198 - 5220）。扩大 基于这些发现，并使用相同的二酰基甘油-内酯（DAG-内酯）模板， 发现了一系列新的含有杂环部分的DAG-内酯（吡啶， 喹啉和吲哚）作为α-亚芳基片段，其显示出与RasGRP3的选择性结合， 与PKC-α相比， 亲和力（J. Med. Chem. 2008，51，5371 - 5386）。已选择两种化合物用于 提交给分子靶向学院的JDC委员会，以进行可能的临床前和 临床研究。几种DAG-内酯的生物物理性质研究 刚性低聚（对苯乙炔）酰基单元探索热力学和结构 这些化合物的特征及其在空气/水界面处的脂质相互作用表明 DAG-内酯主要掺入流体磷脂相中， 比在例如由胆固醇形成的凝聚相中更高（Langmuir 2008，出版中）。

We found that DAG-lactone libraries generated by a solid-phase approach produced a multitude of unique biological activities. Subtle differences in chemical diversity in two areas of the molecule, the combination of which generates what we have termed chemical zip codes, are able to transform a relatively small chemical space into a larger universe of biological activities, as membrane-containing organelles within the cell appear to be able to decode these chemical zip codes. It is postulated that after binding to protein kinase C (PKC) isozymes or other non-kinase target proteins containing diacylglycerol-responsive, membrane-interacting C1 domains, the resulting complexes are directed to diverse intracellular sites where different substrates are accessed. Multiple cellular bioassays show that DAG-lactones, which bind to PKC-alpha, expand their biological repertoire into a larger domain, eliciting distinct cellular responses (J. Med. Chem. 2008, 51, 5198-5220). Expanding on these findings and using the same diacylglycerol-lactone (DAG-lactone) template we discovered a series of novel DAG-lactones containing heterocyclic moieties (pyridines, quinolines and indoles) as alpha-arylidene fragments that show selective binding to RasGRP3 as compared to PKC-alpha by more than two orders of magnitude and with subnanomolar binding affinities (J. Med. Chem. 2008, 51, 5371-5386). Two compounds have been selected for submission to the JDC committee of the Molecular Targets Faculty for possible pre-clinical and clinical investigations. A study on the biophysical properties of some DAG-lactones carrying rigid oligo(p-phenyleneethynylene) acyl units exploring the thermodynamics and structural features of these compounds and their lipid interactions at the air/water interface suggest that the DAG-lactones are predominantly incorporated within fluid phospholipids phases rather than in condensed phases formed, for example, by cholesterol (Langmuir 2008, in press).