| 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-diphenyl-porphyrin, 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 led 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 at 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. |
