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

我们发现，通过固相方法生成的DAG-内酯文库产生了大量独特的生物活性。分子的两个区域的化学多样性的细微差异产生了我们所说的化学邮政编码，能够将相对较小的化学空间转化为更大的生物活动宇宙，因为细胞内含有膜的细胞器似乎能够破译这些化学邮政编码。据推测，在与蛋白激酶C(PKC)同工酶或其他含有二酰基甘油反应、膜相互作用的C1区的非激活靶蛋白结合后，得到的复合体被定向到不同的细胞内位置，在那里可以接触到不同的底物。多种细胞生物测定表明，与PKC-α结合的DAG-内酯将其生物谱系扩展到更大的区域，引起不同的细胞反应(J.Med.化学。2008、51、5198-5220)。在这些发现的基础上，使用相同的二酰基甘油-内酯(DAG-内酯)模板，我们发现了一系列含有杂环基团(吡啶、喹啉和吲哚)的新型DAG-内酯作为α-亚芳基片段，与RasGRP3显示出选择性结合，与PKC-α相比高出两个数量级以上，并具有亚纳摩尔结合亲和力(J.Med)。化学。2008，51,5371-5386)。已经选择了两种化合物提交给分子靶标学院的JDC委员会进行可能的临床前和临床研究。对一些带有刚性低聚(对苯乙撑)酰基单元的DAG-内酯的生物物理性质的研究探索了这些化合物的热力学和结构特征以及它们在空气/水界面上的脂类相互作用，结果表明DAG-内酯主要结合在流动的磷脂相中，而不是在例如由胆固醇形成的凝聚相中(Langmuir 2008，出版社)。

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).