EXPLORATION OF NEW REGIONS OF DIVERSITY SPACE IN ERGOT-BASED LIBRARIES

描述（由申请人提供）：麦角生物碱，可以说是任何类别的天然产物中表现出最大多样性的药理学活性，是产生一系列文库作为新生物靶标探针的理想化学起点。 这类天然存在的成员之间的高密度的生物活性，范围从神经受体激动和拮抗酪氨酸激酶抑制，表明构建类似结构的合成库将产生大量的活性化合物。 麦角林结构上看似很小的变化可以在药理学上产生显著的差异，这一事实也证明了这样一个库将表现出广泛的活性的想法。 目前的项目的目的是通过改变麦角生物碱的两个主要类别：麦角酰胺和棒麦角碱的A（苯基）环上的成分来构建这样一个库。 为了实现这一目标，最近公布的麦角酸核的全合成被用作起点，以设计一种新的路线来麦角酰胺和棒酰胺，其被优化用于文库生产，允许快速合成麦角酸核的变体从苯肼在只有四个步骤或从邻碘苯胺在五个步骤。 作为额外的奖励，该方法允许通过掺入缀合的A环成分来调节麦角酰胺的天然荧光波长，以产生一组具有固有的自报告荧光性质的生物探针。

DESCRIPTION (provided by applicant): Ergot alkaloids, exhibiting what is arguably the greatest diversity of pharmacological activity of any class of natural products, are an ideal chemical starting point from which to produce a range of libraries as probes of new biological targets. The high density of bioactivities among the naturally occurring members of this class, ranging from neuroreceptor agonism and antagonism to tyrosine kinases inhibition, suggests that constructing a synthetic library of analogous structures would yield a large number of active compounds. The fact that seemingly small changes in the structure of ergolines can produce striking differences in pharmacology also lends credence to the idea that such a library would exhibit a wide spectrum of activities. The aims of the current project are to construct such a library by varying constituents on the A (phenyl) ring of the two primary classes of ergot alkaloids: lysergamides and clavinets. In order to achieve this goal, a recently published total synthesis of the lysergic acid nucleus is used as a starting point to design a new route to lysergamides and clavinets which is optimized for library production, allowing rapid synthesis of variants of the lysergic acid nucleus from phenylhydrazines in only four steps or from ortho-iodoanilines in five. As an added bonus, the method allows, through incorporation of conjugated A-ring constituents, for tuning of the natural fluorescence wavelength of lysergamides to yield a set of biological probes with inherent self-reporting fluorescence properties.