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

• 批准号: 10016330
• 负责人: Jennifer Marie Schomaker
• 金额: $ 26.49万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/10016330
• 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

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.

项目总结/文摘: