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New Methodology for Indole Alkaloid Syntheses

吲哚生物碱合成新方法

基本信息

批准号：
8119361
负责人：
KEN S. FELDMAN
金额：
$ 7.72万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-09 至 2012-01-31
项目状态：
已结题

项目摘要

The pursuit of two independent projects in indole synthesis, targeting members of the dragmacidin family of phosphatase inhibitors in one case and the anticancer sponge principle perophoramidine in the other, is proposed. In each case, development of novel methodology for the efficient preparation of the parent ring systems is followed by planned total syntheses of the natural products dragmacidin E and perophoramidine, as well as rationally designed structural analogues of the former species as part of an SAR study. Selective phosphatase inhibition has been proposed as a means of therapeutic intervention in a host of diseases, from Parkinson's to cancer. One key unsolved problem in this area is the identification of small molecules that display significant selectivity for inhibition of the phosphatase PP1 over the analogous phosphatase PP2A. Certain dragmacidins are reported to exhibit such preferences, and the program of synthesis outlined in this proposal is designed to provide molecules for probing the structural basis for this selectivity. A new approach to C(3)/C(4)-cycloheptane-bridged indoles that features sequential Witkop and Dieckmann cyclizations is at the core of the synthesis strategy for these structurally novel compounds. The perophoramidine work will provide useful amounts of this scarce sponge-derived natural product to aid in further evaluation of its anti-cancer properties. This synthesis route extends from a new approach to spirocyclic oxindole derivatives that utilizes an oxidative cyclization of an indolic substrate. Addressing long- standing challenges in indole oxidative cyclization chemistry, such as a lack of regioselective bond formation and product (over)oxidation, are within the purview of the methodology proposed herein. The use of a new variant of the Pummerer reaction to control both oxidation level and reaction site within the indole nucleus forms the basis of this chemistry.

追求两个独立的项目，在吲哚合成，目标成员的dragmacidin家族的磷酸酶抑制剂在一种情况下和抗癌海绵原则perophoramidine在其他情况下，提出了在每种情况下，开发新的方法来有效地制备母环，系统之后是天然产物dragmacidin E和perophoramidine的有计划的全合成，以及作为SAR研究的一部分的前物种的合理设计的结构类似物。选择性磷酸酶抑制已被提出作为一种治疗干预手段，用于治疗许多疾病，从帕金森到癌症。该领域一个尚未解决的关键问题是识别小分子，相对于类似的磷酸酶PP 2A，对磷酸酶PP 1的抑制显示出显著的选择性。据报道，某些dragmacidin表现出这样的偏好，并且本发明中概述的合成程序该提案旨在提供用于探测这种选择性的结构基础的分子。一个新具有连续Witkop和Dieckmann特征的C（3）/C（4）-环庚烷桥连吲哚的方法环化是这些结构新颖的化合物的合成策略的核心。 perophoramidine的工作将提供有用的数量，这种稀缺的海绵衍生的天然产品，以帮助以进一步评估其抗癌特性。这种合成路线从一种新的方法延伸到螺环羟吲哚衍生物，其利用吲哚底物的氧化环化。解决长- 吲哚氧化环化化学中的长期挑战，例如缺乏区域选择性键形成和产物（过）氧化都在本文提出的方法的范围内。使用新的 Pummerer反应的变体，用于控制吲哚核内的氧化水平和反应位点形成了这种化学反应的基础。