SYNTHESES OF LABELED HEMES FOR PROTEIN NMR STUDIES

这项提议的目标是发现基础化学和 获得生物卟啉体系的合成方法学 感兴趣，特别强调同位素方法学的发展 标记血红素，以便提供访问独特的光谱探针的途径 血红素蛋白中的构效关系。方法将是 开发了允许区域选择性地合成天然血红素的产品 在预定的位置标记有氢、碳-13和氮- 15，如果有足够的可用的，这些研究产生的化合物将 随后用于核磁共振、圆二色谱和共振拉曼光谱 了解血红素与载脂蛋白相互作用的研究 多种具有重要生物学意义的结构/功能关系 血红素蛋白，如血红蛋白、肌红蛋白、细胞色素、加氧酶和 过氧化物酶。此外，还提出了合成各种介孔分子筛的设想。 甲基化亚铁血红素(用于亚铁血红素加氧酶研究)，未标记亚铁血红素类似物， 亚铁血红素二聚体和氢化亚铁血红素，以及间断结合的亚铁血红素， 异卟啉体系，以及各种类型的非平面卟啉。我们会 继续研究被称为二亚甲基卟啉的还原卟啉体系和 将进一步发展非常简单和更复杂的方法论 获取卟啉系统。这项拟议的工作将提供一种合成 光谱方法学发展的主干和支点 提高对血红素蛋白功能、结构和功能的认识 导致几种衰弱疾病的电子因素，如 贫血。合成新化合物的两种基本方法将 将被开发；碳-13，氮-15，未标记的卟啉，和中- 甲基卟啉将由无环化合物全合成而成 先驱物。这种方法的一些方法已经制定出来了， 但是，改进和发现新的方法，简单和多步骤，是 有计划也有预期。一些氢标记，碳-13标记 卟啉，原卟啉IX类似物，N-甲基-4-甲基-4-甲基-4，4，4-三甲基-4，4，4，4，4，5，6-三甲基-4 甲基卟啉和其他血红素将通过操纵 现有天然商业可得的卟啉上的取代基。

The objective of this proposal is discovery of fundamental chemistry and synthetic methodology for obtaining porphyrin systems of biological interest, with special emphasis on development of methodology for isotope labeling of hemes so as to provide access to unique spectroscopic probes of structure- activity relationships in heme proteins. Methodology will be developed which will permit synthesis of natural hemes regioselectively labeled in predetermined positions with deuterium, carbon-13, and nitrogen- 15, if sufficient is available, compounds resulting from these studies will subsequently be used for NMR, circular dichroism, and resonance Raman studies to gain an understanding of heme apoprotein interactions and structure/function relationships in a variety of biologically important heme proteins such as hemoglobins, myoglobins, cytochromes, oxygenases, and peroxidases. It is also proposed to synthesize a variety of meso- methylated hemes (for heme oxygenase studies), unlabeled heme analogues, heme dimers, and hydrohemes, as well as hemes with interrupted conjugation, isoporphyrin systems, and non-planar porphyrins of various types. We shall continue studies of reduced porphyrin systems known as porphodimethenes and shall further develop very simple, as well as more complex, methodology for obtaining porphyrin systems. Thr proposed work will provide a synthetic backbone and anchor point for spectroscopic methodology being developed to advance the understanding heme protein function, and of structural and electronic factors which cause several debilitating diseases such as anemias. Two fundamental approaches for synthesis of novel compounds will be developed; carbon-13, nitrogen-15, unlabeled porphyrins, and meso- methylporphyrins will be obtained by total synthesis from acyclic precursors. Some methods for such approaches have already been worked out, but improvements and discovery of new methodology, simple and multistep, is planned and anticipated. Some deuterium labeled, carbon-13 labeled porphyrins, protoporphyrin IX analogues, N-methyl- land meso- methylporphyrins and other hemes will be approached by manipulation of substituents on existing natural commercially available porphyrins.