Combinatorial Chemistry of Porphyrins

描述（由申请人提供）：组合文库在发现新疗法和新材料方面的力量是公认的。该范例是在固体载体上制作定向文库，以便可以选择，鉴定，纯化和表征单个化合物。“获胜”的化合物成为一系列衍生物的母体，这些衍生物经过筛选以增强活性。这种方法的一个问题是，固相文库通常会错过几种化合物在具有多个目标的系统上引起的协同效应。限制对协同效应的搜索的原因是化验数量呈指数增长。由于先导化合物的选择、鉴定、纯化和表征要复杂得多，溶液相文库的开发程度要低得多，而且通常不被使用。在某些情况下，固相法具有优势，例如，当整个细胞是目标时（治疗癌症或特定细胞类型的疾病，对特定组织进行成像或根除细菌）。目标是发展液相组合化学，液相分析方法和液相选择方案，以确定最有希望的化合物补充，这些化合物将对靶细胞发挥最大的协同作用，但新治疗方法的开发并非迫在眉睫

DESCRIPTION (provided by applicant): 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.