MEDICINAL CHEMISTRY OF NOVEL ANTITHROMBOTIC DRUGS

蛋白激酶C(PKC)是一种重要的调节酶，其 生理激活需要它成为膜结合的。这种情况会发生 通过同时存在钙，一种酸性磷脂，如 磷脂酰丝氨酸(PS)和二甘油酯。后者的存在是 具有重要的监管意义，因为它是 聚磷脂酰肌醇周转率。甘油二酯的要求可以是 满足于结构多样化的肿瘤促进剂，如佛波醇 酯、刺青素和去溴青霉毒素。PKC很可能是 是肿瘤促进者的重要靶点。此外，PKC还扮演着一个 在血小板聚集、心功能和神经中的重要作用 功能。这笔赠款的主要重点是了解 PKC的新激活过程。特别值得关注的是 解开PKC激活子功能的结构基础。一对一 另一方面，PKC在化学结构方面具有极高的选择性 甘油二酯激活剂。同时，结构多样化的肿瘤 属于二萜、多肽和大环内酯类系列的启动子可以 它们都能有效地激活这种酶。这些观察结果在这里是一致的 提出了一个新的关于PKC的统一结构假说 基于进度报告中描述的实验的激活剂。 这一新的假说预测了新的双甘油三酯和 应与该激酶有效相互作用的多肽类似物。这些 分子将被合成并研究为可能的PKC激活剂和 抑制剂。最后，将制备新的环状PS类似物来研究 蛋白激酶C磷脂结合部位的特异性。 关于激活剂结合位点的性质的免费研究也在 已经预料到了。PKC调节结构域结合位点将是共价的 以激活剂为基础的光亲和探针标记以及标记区域 将被测序。 综上所述，这些研究应该会让我们更接近于了解 PKC在分子水平上的调控以及如何调控的一般问题 蛋白质可以与膜相互作用，并与膜结合。最后，结构性的 在这里获得的信息将有助于绘制PKC二甘油酯的图谱 结合部位，可作为制备强效物质的起点 酶的抑制剂。

Protein kinase C (PKC) is an important regulatory enzyme whose physiological activation requires it to become membrane-bound. This occurs via the simultaneous presence of calcium, an acidic phospholipid such as phosphatidyl serine (PS), and a diglyceride. The presence of the latter is of great regulatory significance because it is the product of polyphosphatidylinositol turnover. The diglyceride requirement can be satisfied by structurally diverse tumor promoters such as the phorbol esters, teleocidin, and the debromoaplysiatoxins. It is likely that PKC is an important target for the tumor promoters. In addition, PKC plays an important role in platelet aggregation, cardiac function, and neural function. The major focus of this grant is to understand the mechanism of the novel activation process of PKC. Of particular interest is the unravelling the structural basis for PKC activator function. On the one hand, PKC is exceedingly selective with respect to the chemical structure of diglyceride activators. At the same time, structurally diverse tumor promoters belonging to the diterpene, peptide, and macrolide series , can all potently activate the enzyme. These observations are reconciled here with the presentation of a new unifying structural hypothesis on PKC activators which are based on experiments described in the progress report. This new hypothesis makes predictions concerning novel diglyceride and peptide analogs which should potently interact with the kinase. These molecules will be synthesized and studied as putative PKC activators and inhibitors. Finally, novel cyclic PS analogs will be prepared to study the specificity of the phospholipid binding-site of PKC. Complimentary studies on the nature of activator binding-site are also anticipated. The PKC regulatory domain binding-site will be covalently labeled with activator-based photoaffinity probes and the labeled region will be sequenced. Taken together, these studies should bring us closer to an understanding of the regulation of PKC at a molecular level and the general issue of how proteins can interact with and bind to membranes. Finally, the structural information obtained here will serve to map the PKC diglyceride binding-site and can be used as a starting point to prepare potent inhibitors of the enzyme.