Wender P A, Koehler K F, Sharkey N A, Dell'Aquila M L, Blumberg P M
Proc Natl Acad Sci U S A. 1986 Jun;83(12):4214-8. doi: 10.1073/pnas.83.12.4214.
The diterpene diester phorbol 12-myristate 13-acetate and the alkaloid teleocidin B are structurally unrelated natural products that display similar potent irritant and tumor-promoting activities. Computer modeling of these and other structural classes of tumor promoters show a marked similarity in the relative positions of certain heteroatoms and hydrophobic groups. For phorbol this mapping consists of the C-4, C-9, and C-20 hydroxyl groups as well as a hydrophobic region filled by a long-chain acyl functionality attached to either the C-12 or the C-13 positions. Diacylglycerols, thought to be the endogenous activators of the major phorbol ester receptor protein kinase C likewise fit this model in a stereospecific fashion. As an initial test of the utility of the model, members of a new and simplified class of activators were synthesized that possess the predicted essential structural features. These compounds all inhibited specific phorbol ester binding to protein kinase C, albeit with low affinity (10-60 microM); further analysis of one derivative, decylhydroxylindole, confirmed that the inhibition of phorbol ester binding was competitive. This same derivative inhibited epidermal growth factor binding in intact Swiss 3T3 cells and studies with another derivative showed phosphorylation of a 40-kDa protein in platelets. Both of these in vivo responses are characteristic of phorbol esters.
二萜二酯佛波醇12 - 肉豆蔻酸酯13 - 乙酸酯和生物碱远距致癌物B是结构不相关的天然产物，但它们具有相似的强效刺激和促肿瘤活性。对这些及其他结构类型的肿瘤启动子进行计算机建模显示，某些杂原子和疏水基团的相对位置存在显著相似性。对于佛波醇来说，这种映射包括C - 4、C - 9和C - 20羟基，以及一个由连接在C - 12或C - 13位置的长链酰基官能团填充的疏水区域。二酰基甘油被认为是主要佛波醇酯受体蛋白激酶C的内源性激活剂，同样以立体特异性方式符合该模型。作为对该模型实用性的初步测试，合成了一类新的、简化的激活剂，它们具有预测的基本结构特征。这些化合物都能抑制佛波醇酯与蛋白激酶C的特异性结合，尽管亲和力较低（10 - 60微摩尔）；对一种衍生物癸基羟基吲哚的进一步分析证实，佛波醇酯结合的抑制是竞争性的。这种相同的衍生物抑制完整的瑞士3T3细胞中表皮生长因子的结合，对另一种衍生物的研究表明血小板中一种40 kDa蛋白发生了磷酸化。这两种体内反应都是佛波醇酯的特征。
