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Studies towards the synthesis of photosensitizers with improved biodistribution and light-absorbing properties

University of British Columbia

The objective of this work was to develop methods for preparing novel photosensitizer drugs with a) improved selective accumulation in diseased tissue and b) increased wavelengths of activation. The approach taken to enhance selectivity involved exploiting the upregulation of steroid receptors within tumorous cells. Porphyrinic photosensitizers were conjugated to a variety of steroids, ranging from cholesterol to the estrogens and androgens. A number of linking methods were employed: cholesterol was attached at the 3-position via a carbamate group or a diene tether. However, these linkages were non-ideal, as the products lacked the desired stability or existed as geometric isomers, and so improved techniques were sought. This led to the development of a palladium-catalyzed cross-coupling technique to link 10- iodo-5,15-diphenylporphyrin with hormonal steroids ethynyl-substituted at the 17-position. Using this method, a series of steroid-porphyrin conjugates was prepared. In an extension of this work, selective couplings were performed on 5-bromo-15-iodo-10,20-diphenylporphyrin, in which the iodo-group alone reacted under mild conditions. A second coupling under more rigorous conditions resulted in reaction at the bromo-substituent, creating a bifunctionalized porphyrin product. This provides an alternative method to the synthesis of asymmetrically-substituted porphyrins. Efforts at increasing the absorption wavelength of the photosensitizer lead to the design and synthesis of new chlorin systems based on octaethylporphyrin and possessing exocyclic nitrogen-containing rings. Through these studies three new types of chlorin chromophore were prepared, each absorbing above 670 nm. In addition, an unusual dimeric chlorin was unexpectedly formed, for which an X-ray crystal structure was determined. Finally, attempts were made to prepare analogous chlorins based on other porphyrin systems. As initial efforts at synthesizing a tailor-made base porphyrin system were unsuccessful, 5,15-diphenylporphyrin was chosen as the starting material. Studies aimed improving the synthesis of this compound were partially successful. A series of meso-substituted diphenylporphyrin derivatives was prepared in a manner similar to that used for the octaethylporphyrin analogues. However, these derivatives did not give rise to chlorin products.

Thesis/Dissertation

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2009-06-03

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http://hdl.handle.net/2429/8672

Chemistry

University of British Columbia

UBCV

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