Combinatorial Chemistry of Porphyrins

描述（由申请人提供）：组合文库用于发现新疗法和材料的能力是公认的。该范例是在固体支持物上制备定向文库，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，这些衍生物被筛选以增强活性。这种方法的问题是固相库通常错过由几种化合物对具有多个靶标的系统引起的协同效应。限制搜索协同效应的原因是分析数量的指数增长。溶液相库的开发要少得多，并且通常不使用，因为先导化合物的选择、鉴定、纯化和表征要复杂得多。在某些情况下，溶液相方法具有优势，例如当整个细胞是靶时（治疗特定细胞类型的癌症或疾病、特定组织的成像或根除细菌）。目标是开发溶液相组合化学、溶液相分析方法和溶液相选择方案，以鉴定将对靶细胞发挥最大协同作用的最有希望的化合物补充物，但新疗法的开发不是立即的。 目标.另一个目标是进一步了解各种官能团与靶细胞摄取之间的结构-活性关系。假设是：（a）在存在多个靶（例如全细胞）的情况下，组合文库的几个成员之间可能存在协同关系，所述组合文库的几个成员联合收割机以导致与一种化合物相比显著增强的功能;和（B）溶液相文库可以有效地鉴定化合物的这些组合。由于光动力疗法和成像/染色都针对某些细胞群体，因此卟啉类发色团的溶液相文库非常适合于测试这些应用的假设。具体目标是：（1）开发合成方法以制备靶向的卟啉类化合物溶液相组合库;（2）开发分析工具以表征卟啉类化合物溶液相库的多样性，纯度和性质;（3）开发使用靶细胞从溶液相卟啉类化合物库中选择化合物的方法，以及鉴定它们的手段。

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.