Combinatorial Chemistry of Porphyrins

描述(由申请人提供)：组合库在发现新的治疗方法和材料方面的力量得到了很好的认可。这种模式是在固体载体上建立定向文库，以便能够选择、鉴定、纯化和表征单个化合物。获胜的化合物成为一系列经过筛选以增强活性的衍生品的母体。这种方法的一个问题是，固相库通常会错过几种化合物对具有多个目标的系统所引起的协同效应。限制协同效应搜索的原因是检测的数量呈指数级增长。由于先导化合物(S)的选择、鉴定、提纯和表征要复杂得多，所以溶液相库的开发程度要低得多，而且通常不被使用。在某些情况下，溶液相法具有优势，例如，当整个细胞成为靶点时(癌症或特定细胞类型的疾病的治疗、特定组织的成像或根除细菌)。我们的目标是发展溶液相组合化学、溶液相分析方法和溶液相选择方案，以确定对靶细胞发挥最大协同作用的最有希望的化合物补充，但新疗法的开发并不是立竿见影的。 进球。另一个目标是进一步了解不同官能团之间的结构-活性关系和靶细胞的摄取。假设是：(A)在有多个目标的情况下--例如整个细胞--组合文库的几个成员之间可能存在协同关系，它们结合在一起，与一个化合物相比功能显著增强；和(B)溶液相库可以有效地识别这些化合物的组合。由于光动力疗法和成像/染色都是针对特定的细胞群体，因此卟啉类发色团的溶液相库非常适合于检验这些应用的假设。具体目的是验证假设：(1)开发合成方法来制作目标定向的卟啉类化合物的溶液相组合文库；(2)开发分析工具来表征卟啉类化合物的溶液相库的多样性、纯度和性质；(3)开发利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.