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Synthesis of photocleavable photosensitizer-drug complexes Jiang, Michael Yangbo
Abstract
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.
Item Metadata
Title |
Synthesis of photocleavable photosensitizer-drug complexes
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2007
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Description |
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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Extent |
10883903 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-03-10
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0061705
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2007-11
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International