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

描述(申请人提供)：麦角生物碱，展示了可以说是任何一类天然产品中最多样化的药理活性，是生产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具有高密度的生物活性，从神经受体的兴奋和拮抗到酪氨酸激酶的抑制，这表明构建一个类似结构的人工文库将产生大量的活性化合物。麦角林结构看起来很小的变化可以在药理学上产生显着的差异，这一事实也支持了这样一个图书馆将展示广泛活动范围的想法。目前项目的目标是通过改变两类主要麦角生物碱：麦角酰胺和棒状生物碱A(苯环)上的成分来构建这样一个文库。为了实现这一目标，以最近发表的麦角酸核的全合成为起点，设计了一条合成麦角酰胺和棒状化合物的新路线，该路线针对文库生产进行了优化，允许仅用四步从苯肼或从邻碘苯胺在五步内快速合成麦角酸核的变体。作为额外的优点，该方法允许通过掺入共轭A环成分来调谐麦角酰胺的自然荧光波长，以产生一组具有固有的自报告荧光特性的生物探针。

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.