Synthesis of Carbohydrate-Phthalocyanine Conjugates for Biomedical Applications

用于生物医学应用的碳水化合物-酞菁缀合物的合成

• 批准号: 10579707
• 负责人: Joshua Ruppel
• 金额: $ 40.27万
• 依托单位: DAVIDSON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579707
• 关键词: Acetylgalactosamine; Address; Amines; Award; Binding; Biological; Biological Models; Carbohydrates; Cell Death; Cell surface; Chemistry; Clinical; Collaborations; Development; Effectiveness; Electrons; Energy Transfer; Enzymes; Evaluation; Exhibits; Fostering; Generations; Glycoconjugates; Hepatocyte; Hydrophobicity; Hydroxides; Infection; Institution; Lead; Lectin; Libraries; Light; Lipid Peroxidation; Liquid substance; Metabolism; Methodology; Methods; Molecular; Mycobacterium smegmatis; Mycobacterium tuberculosis; Oxygen; PUVA Photochemotherapy; Penetration; Pharmacology; Photosensitizing Agents; Play; Preparation; Primary carcinoma of the liver cells; Property; Protocols documentation; Public Health; Reaction; Reactive Oxygen Species; Research; Resources; Series; Singlet Oxygen; Solubility; Sulfate; Superoxides; System; Therapeutic; Time; Tissues; Training; Trehalose; Tuberculosis; United States National Institutes of Health; Water; Work; absorption; analog; base; biological systems; cancer therapy; cell killing; college; design; experience; improved; innovation; microbial; next generation; overexpression; phthalocyanine; receptor; success; triplet state; undergraduate research; undergraduate student

PROJECT SUMMARY Phthalocyanines are macrocycles that meet all the criteria for an effective photosensitizer including absorption in the near infrared region between 700-1100nm for deep tissue penetration, and high singlet oxygen generation for maximum cell killing. However, the same properties that make phthalocyanines ideal photosensitizers from a photophysical perspective limit their therapeutic applications in biological systems. Phthalocyanines are known to exhibit limited solubility in water, tend to aggregate in biological fluids, and exhibit limited selectivity toward the targeted tissues. Several general approaches have been used to improve the pharmacological profile of phthalocyanines, including functionalization of the isoindole (outer) rings with sulfates or other water-soluble moieties such as quaternary amines. While these approaches have shown some success, their preparation still suffers from inefficient chemistries at key synthetic steps leading to low yielding reaction mixtures that can be difficult to separate and evaluate for pharmacological activity. In addition, the current methods for preparing these phthalocyanines are not readily amenable to tuning (e.g., to create libraries to study their applications in biological systems). Their challenging synthesis has also limited the installation of groups that might be used to enhance the overall selectivity of these compounds. This proposal addresses these issues through the modular synthesis of glycoconjugated phthalocyanines (GPc’s). In addition to providing enhanced solubility, carbohydrates with targeting ability (e.g., through the direct binding of lectins that are overexpressed on cell surface, or through the engagement of carbohydrate binding enzymes that play key roles in metabolic processes) can be used to enhance selectivity. Our innovative methodology, which will allow us to prepare libraries of GPc’s, relies on the synthesis of readily accessible phthalocyanine-based bromosynthons which can be selectively substituted with linkers bearing functional handles for glycoconjugation. In this way, both the linker and carbohydrate can be exchanged to tune the system for a desired biological application. In this proposal we also explore the ability of the GPc’s we synthesize to address two global public health issues in line with NIH initiatives: hepatocellular carcinoma and tuberculosis. Given our experience, long-standing successful collaboration, and combined expertise and resources, we, as multiple PIs from Davidson College and USC-Upstate, are uniquely qualified to co-lead this effort, which will be our second R15 initiative together. This R15 AREA proposal will support an exceptional research experience for multiple undergraduates at each institution and foster the training of the next generation of synthetic chemists.

项目总结 酞菁是满足包括吸收在内的有效光敏剂的所有标准的大环 在700-1100 nm之间的近红外区域，用于组织的深层渗透和高单线态氧产生 最大限度地杀灭细胞。然而，使酞菁成为理想的光敏剂的相同性质来自 光物理的角度限制了它们在生物系统中的治疗应用。已知的是酞菁 在水中表现出有限的溶解性，倾向于在生物液体中聚集，并且对 目标组织。几种常用的方法已被用来改善其药理作用 酞菁，包括硫酸盐或其他水溶性的异吲哚(外)环的官能化 季胺等部分。虽然这些方法取得了一些成功，但它们的准备工作仍然 在关键的合成步骤中化学反应效率低下，导致低产率的反应混合物 难以分离和评价药理活性。此外，目前制备这些材料的方法 酞菁不容易调节(例如，创建文库来研究它们在生物中的应用 系统)。它们具有挑战性的合成也限制了可能用于增强 这些化合物的总体选择性。该方案通过模块化综合来解决这些问题 糖共轭酞菁(GPC‘s)。除了提供更高的溶解度外，碳水化合物还具有 靶向能力(例如，通过直接结合在细胞表面过度表达的凝集素，或通过 在代谢过程中起关键作用的碳水化合物结合酶的参与)可用于 增强选择性。我们的创新方法将允许我们准备GPC的库，依赖于 可选择性取代的易得酞菁基溴合成酮的合成 带有用于糖结合的功能性手柄的连接子。通过这种方式，连接物和碳水化合物都可以 交换以调整系统以用于所需的生物应用。在这份提案中，我们还探讨了 根据美国国立卫生研究院的倡议，我们综合GPC来解决两个全球公共卫生问题：肝细胞 癌症和肺结核。鉴于我们的经验，长期成功的合作，并结合 专业知识和资源，作为来自戴维森学院和南加州大学北部的多名PI，我们是唯一有资格 共同领导这项工作，这将是我们共同发起的第二个R15计划。此R15区域提案将支持 为每所院校的多名本科生提供卓越的研究经验，并促进对下一代的培训 一代合成化学家。