SYNTHESIS AND CHARACTERIZATION OF FORSKOLIN DERIVATIVES

毛喉素衍生物的合成和表征

• 批准号: 3804708
• 负责人: J ROBBINS
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3804708
• 关键词: adenylate cyclase; affinity labeling; alkylating agents; antineoplastics; chemical binding; chemical structure function; chemical synthesis; forskolin; iodination; isothiocyanates; ligands

Forskolin interacts with a number of membrane proteins that appear to be structurally similar. By modifying forskolin at different sites of the molecule, intermediates were synthesized that are stable, easily derivatized, and have high affinities for different membrane proteins. For example, 7-(2-aminoethyl)aminocarbonyl-forskolin (7-AEC-Fsk), shows high affinity for the glucose transporter. In contrast, 6-(2- aminoethyl)carbonylforskolin, 6-AEC-Fsk, has high affinity for adenylyl cyclase and does not interact with the glucose transporter. Iodinated derivatives of these intermediates were prepared and used as ligands for assaying binding to adenylyl cyclase or the glucose transporter. Radiolabeled ligands were prepared from the two intermediates to develop ligand binding assays for adenylyl cyclase and the glucose transporter. Another intermediate was prepared from forskolin, 1-deoxy-1-(2 aminoethyl)aminoforskolin, 1-AEC-1-deoxyforskolin, to make a radiolabeled ligand to assay bacterial pentose transporters. The bromoacetyl and isothiocyanate alkylating derivatives of 6-AEC-Fsk and 7-AEC-Fsk were prepared. Both bromoacetyl derivatives exhibited irreversible binding to adenylyl cyclase and not to the glucose transporter. The isothiocyanates showed similar specificity though were less potent than the bromoacetyl derivatives at adenylyl cyclase. The aminoethylcarbamate derivative of the anticancer drug estramustane was synthesized. This was used to synthesize an iodinated photoaffinity label to study the interaction of extramustane with microtubule proteins.

毛喉素与一些膜蛋白，似乎是相互作用的 结构相似。 通过修饰毛喉素在不同的网站， 分子，合成了稳定，容易 衍生化的，并且对不同的膜蛋白具有高亲和力。 为 例如，7-（2-氨基乙基）氨基羰基-毛喉素（7-AEC-Fsk），显示出高的 对葡萄糖转运蛋白的亲和力。 相比之下，6-（2- 氨乙基）羰基福司可林，6-AEC-Fsk，对腺苷酰具有高亲和力， 环化酶，不与葡萄糖转运蛋白相互作用。 碘化 制备了这些中间体的衍生物，并用作 测定与腺苷酸环化酶或葡萄糖转运蛋白的结合。 从这两个中间体制备放射性标记配体， 腺苷酸环化酶和葡萄糖转运蛋白的配体结合试验。 另一种中间体是由毛喉素，1-脱氧-1-（2 氨基乙基）氨基毛喉素、1-AEC-1-脱氧毛喉素，以制备放射性标记的 配体来测定细菌戊糖转运蛋白。 6-AEC-Fsk的溴乙酰基和异硫氰酸酯烷基化衍生物和 制备7-AEC-Fsk。 两种溴乙酰衍生物均表现出 不可逆结合腺苷酸环化酶，而不是葡萄糖 传送器。 异硫氰酸酯显示出相似的特异性， 在腺苷酸环化酶上的效力低于溴乙酰衍生物。 抗癌药物雌莫司坦的氨基乙基氨基甲酸酯衍生物， 合成了 这被用来合成碘化的光亲和标记物 研究extramustane与微管蛋白的相互作用。