Method Development for the Synthesis of Glycoconjugated-Phthalonitriles and A3B Glycoconjugated-Phthalocyanines
Document Type
Event
Abstract
Photodynamic Therapy (PDT) is a process that can potentially lead to cell death through the light activation of a photosensitizer molecule. PDT has potential applications as a cancer therapy or as an antibiotic through the use of these photosensitizer’s which may provide selectivity to diseased tissues. A photosensitizer is a molecule that when activated by this exposure to certain wavelengths of light, produces reactive oxygen species (ROS). The ROS is typically oxygen radicals that can damage cells and in theory, leads to apoptotic pathways. Phthalocyanines are of particular interest as a photosensitizer in PDT due to a high absorbance in the wavelengths that are of clinical interests but typically suffer from poor solubility in biological fluids. The goal of this project was to develop methods to synthesize glycoconjugated-phthalocyanines from a library of glycoconjugated-phthalonitrile derivatives. An attachment of a carbohydrate (glycoconjugation) would, in theory, increase phthalocyanine’s bioavailability since carbohydrates are more readily soluble. The development of a method to synthesize glycoconjugated-phthalocyanines would open potential pathways for their use as a photosensitizer with applications in PDT. Two methods of synthesis were considered: pre-functionalization and post-functionalization, which refers to the attachment of the carbohydrate before or after the phthalocyanine synthesis. After consideration, the synthesis was conducted using the pre-functionalization approach due to Pc solubility presenting a major obstacle for the post-functionalization technique. To synthesize a glycoconjugated-phthalocyanine, a phthalonitrile derivative, 4-nitrophthalonitrile, was combined with an alcohol linker containing a terminal triple bond via a SNAr reaction. The resulting alkynylated-phthalonitriles were then subjected to glycoconjugation through a copper-catalyzed “click” reaction. This reaction forms a triazole ring with the triple bond of the alkynylated-phthalonitrile and an azide group bonded to a carbohydrate. Azido-carbohydrates used in this study include glucose, galactose, lactose, glucose-NAc, and galactose-NAc. Glycoconjugations resulting from the click reaction were highly efficient and provided excellent to high yields across a number of carbohydrates employed. The synthesis of a glycoconjugated-phthalocyanine was attempted by combining the glucose-glycoconjugated phthalonitrile with a subphthalocyanine, a phthalocyanine precursor, which yielded mixed results due to purification issues. In conclusion, we have proposed a highly efficient method for the synthesis of glycoconjugated-phthalonitriles and a proof of concept for the synthesis of glycoconjugated-phthalocyanines. In the future, we will continue to optimize the synthesis of the glycoconjugated-phthalocyanines and explore alternate synthetic pathways that may lead to higher yields and easier purification protocols.
Method Development for the Synthesis of Glycoconjugated-Phthalonitriles and A3B Glycoconjugated-Phthalocyanines
Breakout Session B: Chemical Sciences
CASB 102Photodynamic Therapy (PDT) is a process that can potentially lead to cell death through the light activation of a photosensitizer molecule. PDT has potential applications as a cancer therapy or as an antibiotic through the use of these photosensitizer’s which may provide selectivity to diseased tissues. A photosensitizer is a molecule that when activated by this exposure to certain wavelengths of light, produces reactive oxygen species (ROS). The ROS is typically oxygen radicals that can damage cells and in theory, leads to apoptotic pathways. Phthalocyanines are of particular interest as a photosensitizer in PDT due to a high absorbance in the wavelengths that are of clinical interests but typically suffer from poor solubility in biological fluids. The goal of this project was to develop methods to synthesize glycoconjugated-phthalocyanines from a library of glycoconjugated-phthalonitrile derivatives. An attachment of a carbohydrate (glycoconjugation) would, in theory, increase phthalocyanine’s bioavailability since carbohydrates are more readily soluble. The development of a method to synthesize glycoconjugated-phthalocyanines would open potential pathways for their use as a photosensitizer with applications in PDT. Two methods of synthesis were considered: pre-functionalization and post-functionalization, which refers to the attachment of the carbohydrate before or after the phthalocyanine synthesis. After consideration, the synthesis was conducted using the pre-functionalization approach due to Pc solubility presenting a major obstacle for the post-functionalization technique. To synthesize a glycoconjugated-phthalocyanine, a phthalonitrile derivative, 4-nitrophthalonitrile, was combined with an alcohol linker containing a terminal triple bond via a SNAr reaction. The resulting alkynylated-phthalonitriles were then subjected to glycoconjugation through a copper-catalyzed “click” reaction. This reaction forms a triazole ring with the triple bond of the alkynylated-phthalonitrile and an azide group bonded to a carbohydrate. Azido-carbohydrates used in this study include glucose, galactose, lactose, glucose-NAc, and galactose-NAc. Glycoconjugations resulting from the click reaction were highly efficient and provided excellent to high yields across a number of carbohydrates employed. The synthesis of a glycoconjugated-phthalocyanine was attempted by combining the glucose-glycoconjugated phthalonitrile with a subphthalocyanine, a phthalocyanine precursor, which yielded mixed results due to purification issues. In conclusion, we have proposed a highly efficient method for the synthesis of glycoconjugated-phthalonitriles and a proof of concept for the synthesis of glycoconjugated-phthalocyanines. In the future, we will continue to optimize the synthesis of the glycoconjugated-phthalocyanines and explore alternate synthetic pathways that may lead to higher yields and easier purification protocols.