The power of combinatorial libraries for the discovery of new therapeutics and material is well recognized. The paradigm is to make directed libraries on solid supports so that an individual compound can be selected, identified, purified, and characterized. The 'winning' compound becomes the parent of a family of derivatives that are screened for enhanced activity. A problem with this approach is that solid phase libraries generally miss synergistic effects elicited by several compounds on systems with multiple targets. The reason to limit searches for synergistic effects is the exponential increase in the number of assays. Solution phase libraries are much less developed and are generally not used because the selection, identification, purification, and characterization of the lead compound(s) are much more complex. There are cases where the solution phase method affords advantages, e.g. when entire cells are targets (treatment of cancer or diseases of specific cell types, imaging of specific tissues, or eradication of bacteria). The goal is to develop the solution phase combinatorial chemistry, solution phase analytical methods, and solution phase selection schemes to identify the most promising complement of compounds which will exert the maximal synergistic effects on target cells, but development of new therapeutics is not the immediate goal. Another goal is to further understand structure-activity relationships between various functional groups and uptake by target cells. The hypothesis is: (a) in cases when there are multiple targets--e.g. whole cells--there may be synergistic relationships between several members of a combinatorial library that combine to result in significantly enhanced function compared to one compound; and (b) solution phase libraries can efficiently identify these combinations of compounds. Since both photodynamic therapy and imaging/staining are directed at certain cell populations, solution phase libraries of porphyrinoids chromophores are ideally suited to test the hypothesis for these applications.
The specific aims to test the hypothesis: (1) Develop synthetic methods to make target-directed solution phase combinatorial libraries of porphyrinoids; (2) Develop analytical tools to characterize the diversity, purity, and properties of solution phase libraries of porphyrinoids; (3) Develop methods using target cells to select compounds from solution phase porphyrinoid libraries, and the means to identify them.
Showing the most recent 10 out of 202 publications
