Porphyrin Synthetic Methods for Bioorganic Applications

用于生物有机应用的卟啉合成方法

• 批准号: 6988480
• 负责人: JONATHAN SIDNEY LINDSEY
• 金额: $ 32.65万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988480
• 关键词: Mossbauer spectrometry; Raman spectrometry; biomimetics; biotechnology; chemical conjugate; chemical models; chemical stability; chemical substitution; chemical synthesis; chlorin; enzyme activity; flow cytometry; method development; porphyrin structure; porphyrins; reagent /indicator; tissue /cell culture; water solubility

The long-term objective of this proposal is to develop synthetic methodology that can be used to gain deep insight into the biological properties of porphyrinic molecules and can be exploited in diagnostic and therapeutic applications. The term "porphyrinic" encompasses tetrapyrrole macrocycles that are fully unsaturated (porphyrins) or partially reduced (hydroporphyrins; such as chlorins or bacteriochlorins). The specific objective is to develop powerful routes for the synthesis of water-soluble, bioconjugatable porphyrins and hydroporphyrins. Hydroporphyrins absorb strongly in the red/near-IR spectral region, an ideal wavelength of light for deep penetration of cells and tissues. Such compounds are anticipated to have widespread biological applications where active targeting with a red/near-IR label is required, yet hydroporphyrins with the requisite molecular design features have not been available synthetically. The hydroporphyrins will bear one conjugatable handle, one or more water-solubilizing groups, structural features to prevent dehydrogenation and suppress oxidation, and tunable photochemistry via alteration of the centrally coordinated metal. Strategies for the rational synthesis of bacteriochlorins will be developed, including the derivatization of porphyrins, the derivatization of chlorins, and synthesis de novo. In the development of new synthetic routes, attention will be paid to issues of simplicity, scope, and scale, thereby enabling widespread utilization by a broad range of scientists from diverse fields. New molecular motifs will be investigated for achieving water solubility, a key requirement for use in biomolecule labeling studies. The basic science for the use of hydroporphyrin-biomolecule conjugates will be addressed by first characterizing the intrinsic properties of the hydroporphyrins, then characterizing the loading, non-covalent binding, aggregation, photostability, and brightness of hydroporphyrin-antibody conjugates. This work will open the door to applications such as multicolor/multiparameter labeling of cells and intracellular components, and provide a sound basis for the design and development of next-generation molecules for use in diverse therapeutic applications where active-targeting strategies are sought.

该提案的长期目标是开发可用于深入了解卟啉分子生物学特性并可用于诊断和治疗应用的合成方法。术语“卟啉的”包括完全不饱和的（卟啉）或部分还原的（氢卟啉;如二氢卟啉或细菌绿素）四吡咯大环。具体目标是开发用于合成水溶性的、可生物缀合的卟啉和氢化卟啉的强有力的路线。氢化卟啉在红色/近红外光谱区域中吸收强烈，这是用于深入穿透细胞和组织的光的理想波长。预计此类化合物具有广泛的生物学应用，其中需要红色/近红外标记的主动靶向，但尚未合成具有必要分子设计特征的氢卟啉。氢化卟啉将带有一个可缀合的柄、一个或多个水增溶性基团、防止脱氢和抑制氧化的结构特征以及通过改变中心配位金属的可调光化学。本论文将探讨菌绿素的合理合成策略，包括卟啉衍生化、二氢卟酚衍生化及从头合成。在开发新的合成路线时，将注意简单性，范围和规模的问题，从而使来自不同领域的广泛科学家能够广泛使用。将研究新的分子基序以实现水溶性，这是用于生物分子标记研究的关键要求。使用氢卟啉-生物分子缀合物的基础科学将通过首先表征氢卟啉的固有性质，然后表征氢卟啉-抗体缀合物的负载、非共价结合、聚集、光稳定性和亮度来解决。这项工作将打开大门的应用，如细胞和细胞内成分的多参数/多参数标记，并提供了一个良好的基础，为下一代分子的设计和开发，用于在不同的治疗应用中寻求主动靶向策略。