Porphyrin Synthetic Methods for Bioorganic Applications

这项提议的长期目标是开发可用于深入了解卟啉分子的生物学特性并可用于诊断和治疗应用的合成方法学。术语“卟啉”包括完全不饱和的(卟啉)或部分还原的(氢卟啉；如氯素或细菌素)的四吡咯大环。其具体目标是开发合成水溶性、生物可结合的卟啉和氢卟啉的有效途径。氢卟啉在红色/近红外光谱区有很强的吸收，这是深入穿透细胞和组织的理想波长。这类化合物有望具有广泛的生物学应用，需要具有红色/近红外标记的活性靶标，但具有必要的分子设计特征的氢卟啉尚未合成出来。氢卟啉将带有一个可结合的手柄、一个或多个溶水基团、防止脱氢和抑制氧化的结构特征，以及通过中心配位金属的变化而可调的光化学。将开发合理合成细菌素的策略，包括卟啉的衍生化、氯化的衍生化和从头合成。在开发新的合成路线时，将注重简单性、范围和规模的问题，从而使来自不同领域的广泛的科学家能够广泛使用。将研究新的分子基序以实现水溶性，这是生物分子标记研究中使用的关键要求。使用氢卟啉-生物分子偶联物的基础科学将首先表征氢卟啉的固有性质，然后表征氢卟啉-抗体偶联物的负载量、非共价结合、聚集、光稳定性和亮度。这项工作将为细胞和细胞内成分的多色/多参数标记等应用打开大门，并为设计和开发下一代分子提供良好的基础，这些分子用于寻求主动靶向策略的各种治疗应用。

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.