Synthesis of Carbohydrate-Phthalocyanine Conjugates for Biomedical Applications

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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.