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.

“不寻常的药理和交叉偶联的新工具”的摘要，5R35GM122606 细胞的生物测定引导分馏发现在新的和出乎意料的方式。这些细胞代谢产物从进化中出现，具有复杂的分子特征先前进行功能。高立体化学内容，高球形和潜水杂原子含量比简单，平坦和非极性物质。大分子文库的参数化支持了进化之间的相关性优化和热设计：“药物”化学空间远离商业建筑块和天然产物（NP空间）。这些类型的分子代表了化学的挑战但是，合成，需要开发新的化学工具以优化和人类使用。这笔赠款将我们的工作促进了NP空间的快速访问和导航。我们的强大通往复杂分子的途径已被证明是实用的：合成使我们能够注释并修改生物学功能。在接下来的赠款期内，我们将此方法扩展到三个领域。首先，我们发展化学以获取具有已知表型效应但未知生物学靶标的化学型的化学型。一目标刺激了新的立体选择性交叉耦合反应的发现，而另一个则具有启发了将惰性脚手架转换为新的弹头，以增加蛋白质。第二，我们描述快速访问已知生物学靶标的复杂配体，这些靶标体现了多个的“组合”聚集体蛋白质。复杂小分子的各种结构修改将使搜索选择性在这些组合目标中，对热发育产生了影响。第三，选择性定义双催化交叉耦合以达到NP空间的未来目标：我们试图解决基材选择性，相对定位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.