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Synthetic approaches to complex amines that inhibit protein synthesis by impacting the ribosome

通过影响核糖体抑制蛋白质合成的复杂胺的合成方法

基本信息

批准号：
10470244
负责人：
Jennifer Marie Schomaker
金额：
$ 26.55万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470244
关键词：
3-hydroxybutanal Alcohols Amination Amines Amino Sugars Anthracycline Antibiotics Antimalarials Binding Binding Sites Biological Biological Assay Carbon Cardiotoxicity Cells Chagas Disease Chemicals Chiroptera Collaborations Complex Coupled Coupling DNA Disease Doxorubicin Drug resistance Electrostatics Environment Eukaryotic Cell Evaluation Exhibits Funding Generations Hybrids Hydrogen Bonding Hydrophobicity Laboratories Lead Libraries Major Groove Malaria Menogaril Methods Minor Groove Mitochondria Multi-Drug Resistance Natural Products Pharmaceutical Chemistry Pharmaceutical Preparations Positioning Attribute Primary carcinoma of the liver cells Protein Biosynthesis Resistance development Ribosomes Role Route Secure Structure-Activity Relationship Tetracyclines Therapeutic Therapeutic Agents Toxic effect Triad Acrylic Resin Tuberculosis Universities Wisconsin Work analog anticancer activity antitumor agent antitumor drug base behavior influence bioactive natural products cancer therapy computer studies design drug discovery experience experimental study flexibility functional group insight interest novel open innovation pathogen professor programs propadiene scaffold small molecule stereochemistry tumor

项目摘要

Project Summary/Abstract: Our work in the previous funding period was inspired by synthetic challenges inherent in molecules that directly bind to the ribosome or indirectly impact its function. Structure-activity relationship studies are difficult in these classes of molecules, due to lack of flexible synthetic methods to enable flexible changes to the positioning, stereochemistry and steric environments of key amine and alcohol groups that engage in H- bonding or electrostatic interactions with the binding site; the same is true for altering alkyl and aryl groups that participate in hydrophobic or π-π interactions. Our versatile methods streamline syntheses of stereochemically complex amine 'triads' present in natural products that inhibit protein synthesis, including aminocyclitols, anthracyclines, and tetracyclines. This enables us to construct 'unnatural products' inspired by bioactive natural products, where diversity can be achieved in: 1) heteroatoms installed in the amine 'triad' building blocks, 2) stereochemical relationships amongst the three contiguous, heteroatom-bearing sp3 carbon centers of the triad, and 3) densely functionalized carbo- and heterocyclic scaffolds. A library of >1000 unique compounds in novel amine chemical space displaying significant stereochemical complexity has shown promising activities against drug-resistant malaria and tuberculosis, Chaga's disease, hepatocellular carcinoma, and other biological targets. This renewal builds on our expertise in securing complex, densely functionalized amine motifs to investigate structure-activity relationships in molecules that impact protein synthesis, primarily through interactions with the ribosome. Analogs of the potent antimalarial natural product jogyamycin will be prepared to probe how binding to the ribosome is impacted; these studies are key to the design of simpler synthetic amine scaffolds that show similar bioactivity, but better selectivity for parasitic vs. eukaryotic mitochondrial ribosomes, lowered toxicity, and less propensity to develop resistance. In the same manner, our expertise in complex amine synthesis will be applied to the design of 'hybrid' anthracyclines that mitigate the toxicity and multi-drug resistance seen in the widely-used antitumor drug doxorubicin (DOX) and other related drugs of significance to the treatment of cancer. We have secured the aid of several collaborators to assess the biological activities of our compounds and provide insight into the design of 2nd-generation libraries, including the Eli Lilly Open Innovation program, GSK (in progress), Corteva Agrisciences, several academic colleagues (Prof. Taifo Mahmud, Prof. Dev Arya, Prof. Silvia Cavagnero, Dr. Desiree Bates), and the University of Wisconsin Medicinal Chemistry Center.

项目概要/摘要：我们在上一个资助期的工作受到分子固有的合成挑战的启发，直接与核糖体结合或间接影响其功能。结构-活性关系研究是困难的在这些类别的分子中，由于缺乏灵活的合成方法来实现对分子的灵活改变，定位，立体化学和空间环境的关键胺和醇基团，从事H- 与结合位点的键合或静电相互作用;改变烷基和芳基也是如此，参与疏水或π-π相互作用。我们的多功能方法简化了立体化学合成存在于天然产物中的复合胺“三元组”，其抑制蛋白质合成，包括氨基环醇，蒽环类和四环素类。这使我们能够构建“非天然产品”的灵感来自生物活性的天然产品，其中多样性可以在以下方面实现：1）安装在胺“三元组”结构单元中的杂原子，2）的三个连续的、带有杂原子的sp3碳中心之间的立体化学关系。三元组，和3）密集官能化的碳和杂环支架。超过1000种独特化合物的库，新型的胺化学空间显示出显著的立体化学复杂性，显示出有前途的活性针对抗药性疟疾和结核病、查加病、肝细胞癌和其他生物目标。这次更新建立在我们在确保复杂的，密集的官能化胺基序的专业知识，以研究影响蛋白质合成的分子中的结构-活性关系，主要通过与蛋白质的相互作用，核糖体将制备有效抗疟天然产物乔吉霉素的类似物，这些研究是设计更简单的合成胺支架的关键，生物活性相似，但对寄生虫与真核生物线粒体核糖体的选择性更好，毒性降低，和更少的产生耐药性的倾向。同样，我们在复杂胺合成方面的专业知识将应用于设计“杂合”蒽环类抗生素，以减轻毒性和多药耐药性，广泛使用的抗肿瘤药物阿霉素（DOX）和其他相关药物对治疗癌我们已经获得了几个合作者的帮助，以评估我们化合物的生物活性。并提供对第二代图书馆设计的见解，包括礼来公司的开放创新计划， GSK（进行中）、Corteva Agrisciences、几位学术同事（Taifo Mahmud教授、Dev Arya教授、教授Silvia Cavagnero，Desiree Bates博士）和威斯康星州大学药物化学中心。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（2）

α-Tetrasubstituted Aldehydes through Electronic and Strain-Controlled Branch-Selective Stereoselective Hydroformylation.

DOI：
10.1021/acs.joc.8b01431
发表时间：
2018-09-07
期刊：
The Journal of organic chemistry
影响因子：
0
作者：
Eshon J;Foarta F;Landis CR;Schomaker JM
通讯作者：
Schomaker JM

Regioselective Intramolecular Allene Amidation Enabled by an EDA Complex*.

DOI：
10.1002/chem.202002533
发表时间：
2020-11-02
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
0
作者：
Liu L;Ward RM;Schomaker JM
通讯作者：
Schomaker JM

1,4-Diazaspiro[2.2]pentanes as a flexible platform for the synthesis of diamine-bearing stereotriads.

DOI：
10.1021/jo3000282
发表时间：
2012-03-02
期刊：
The Journal of organic chemistry
影响因子：
0
作者：
Rigoli JW;Boralsky LA;Hershberger JC;Marston D;Meis AR;Guzei IA;Schomaker JM
通讯作者：
Schomaker JM

Diastereoselective Au-Catalyzed Allene Cycloisomerizations to Highly Substituted Cyclopentenes.