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UBC Theses and Dissertations

Synthesis of photocleavable photosensitizer-drug complexes Jiang, Michael Yangbo


The objective of this work was to develop a "photodynamic" site-specific drug delivery methodology, whereby a drug can be released by visible light at the site of irradiation. This goal was fulfilled by connecting the target drug molecule with a photosensitizer through a specially-designed double-bond linkage. Upon visible light illumination, the photosensitizer moiety of the final complex converted ground-state oxygen to the high energized singlet oxygen, which can oxidatively cleave the olefin linkage to release the drug via a tandem [2+2] cyvloaddition-dioxetane decomposition process. Our first synthetic strategy was to combine bioactive carboxylic acids with alkynylporphyrins using a ruthenium-catalyzed addition reaction. However, the preparation of the alkynylporphyrin substrate was unsuccessful. An alternative synthesis was proposed by adding the carboxylic acid to ethoxyacetylene first, but the subsequent Heck coupling of the resulting alkene to porphyrins failed as well. However, an interesting reaction intermediate 11-21-Zn was isolated and characterized by X-ray crystallography. Its formation mechanism and catalytic activity were also studied. The first generation complexes were successfully synthesized using the linker molecule 111-15. Esters as drug mimics were first attached to the linker to form an enol ether linkage by Takai alkylidenation and photosensitizers were then attached by esterification. Visible light illumination of all four complexes gave the desired [2+2] cycloaddition and dioxetane cleavage products in yields from less than 5% to as high as 60%. However, products from the "ene" reaction usually predominated in the photooxygenation. The second generation linker molecule IV-7 was synthesized to facilitate the assembly of the complexes by Takeda alkoxymethylenation and esterification. Using this strategy, drug molecules (carboxylic acid derivatives) were incorporated through an enediol ether or (β-amino enol ether linkage to give the final complexes as a mixture of Z- and E-stereomers. Despite the unimpressive photooxygenation results of most E-isomers, a complete [2+2] cycloaddition selectivity was observed in the photooxygenation of the Z-isomers, due to the cis-directing effects of the olefin hetero-substituents. Aliphatic and aromatic esters, including methyl esters of ibuprofen and naproxen, lactones, and amides have been successfully incorporated and quantitatively (or near quantitatively) released using this strategy.

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