Unusual Pharmacophores and New Tools for Cross-Coupling

不寻常的药效团和交叉偶联的新工具

基本信息

批准号：
10799441
负责人：
Ryan Ashok Shenvi
金额：
$ 7.13万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2027-03-31
项目状态：
未结题

项目摘要

Abstract of “Unusual Pharmacophores and New Tools For Cross-Coupling,” 5R35GM122606 Bioassay-guided fractionation of cells uncovers small molecules that bind receptors in new and unexpected ways. These cellular metabolites emerge from evolution with complex molecular features preoptimized for function. High stereochemical content, high globularity and diverse heteroatom content impart greater specificity of protein binding and greater aqueous solubility than simple, flat and non-polar substances. Parametrization of large molecular libraries have supported a correlation between evolutionary optimization and therapeutic design: “drug” chemical space is optimized away from commercial building blocks and towards natural products (NP space). These types of molecules represent a challenge to chemical synthesis, however, and require the development of new chemical tools for optimization and human use. This grant advances our work towards the rapid access and navigation of NP space. Our robust routes to complex molecules have proven practical: synthesis allowed us to annotate and modify biological function. Over the coming grant period we extend this approach into three areas. First, we develop the chemistry to access two chemotypes with known phenotypic effects but unknown biological targets. One target has stimulated the discovery of a new, stereoselective cross-coupling reaction, whereas another has inspired the conversion of inert scaffolds to new warheads for protein adduction. Second, we describe rapid access to complex ligands of known biological targets that embody ‘combinatorial’ aggregates of multiple proteins. Diverse structural modifications of the complex small molecule will enable a search for selectivity among these combinatorial targets with consequences for therapeutic development. Third, selectivity defines the future goals of dual-catalytic cross-couplings to reach NP space: we seek to address substrate selectivity, relative stereoselectivity and absolute stereoselectivity.

“不寻常的药效团和交叉偶联的新工具”摘要，5R35GM122606 生物测定引导的细胞分级分离发现了与新的和新的受体结合的小分子这些细胞代谢物以复杂的分子特征进化而来。高立体化学含量、高球形度和多样化的杂原子含量。与简单、平面和非极性相比，具有更高的蛋白质结合特异性和更大的水溶性大型分子库的参数化支持了进化之间的相关性。优化和治疗设计：“药物”化学空间远离商业建筑进行优化块和天然产物（NP空间）这些类型的分子代表了对化学的挑战。然而，合成需要开发新的化学工具来优化和人类使用。这笔赠款推动了我们对 NP 空间的快速访问和导航的工作。通往复杂分子的途径已被证明是可行的：合成使我们能够注释和修改生物在接下来的资助期内，我们将这种方法扩展到三个领域。化学来获得两种具有已知表型效应但未知生物靶标的化学型。目标刺激了一种新的立体选择性交叉偶联反应的发现，而另一个目标则刺激了一种新的立体选择性交叉偶联反应的发现。激发了将惰性支架转化为用于蛋白质加合的新弹头的作用。其次，我们描述了快速。获得已知生物靶标的复杂配体，这些配体包含多个“组合”聚集体复杂小分子的多种结构修饰将有助于寻找选择性。这些组合目标对治疗发展产生影响。第三，选择性。定义了双催化交叉偶联达到 NP 空间的未来目标：我们寻求解决底物问题选择性、相对立体选择性和绝对立体选择性。

项目成果

期刊论文数量（33）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Natural Product Synthesis through the Lens of Informatics.

通过信息学的视角进行天然产物合成。

DOI：
10.1021/acs.accounts.0c00791
发表时间：
2021
期刊：
Accounts of chemical research
影响因子：
18.3
作者：
Woo,Stone;Shenvi,RyanA
通讯作者：
Shenvi,RyanA

Change the channel: CysLoop receptor antagonists from nature.

DOI：
10.1002/ps.6166
发表时间：
2021-08
期刊：
Pest management science
影响因子：
4.1
作者：
Tong G;Baker MA;Shenvi RA
通讯作者：
Shenvi RA

Synthetic, Mechanistic, and Biological Interrogation of Ginkgo biloba Chemical Space En Route to (-)-Bilobalide.

DOI：
10.1021/jacs.0c08231
发表时间：
2020-10-28
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Demoret RM;Baker MA;Ohtawa M;Chen S;Lam CC;Khom S;Roberto M;Forli S;Houk KN;Shenvi RA
通讯作者：
Shenvi RA

Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction.