Cyanobacterial pseudo-natural products for anticancer drug discovery

用于抗癌药物发现的蓝藻伪天然产物

• 批准号: 10332782
• 负责人: Eduardo Javier Caro
• 金额: $ 15万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10332782
• 关键词: Address; Antibody-drug conjugates; Antineoplastic Agents; Architecture; Artificial Intelligence; Biological; Biological Assay; Biological Process; Cancer cell line; Cells; Characteristics; Chemicals; Chemistry; Coupled; Coupling; Cyanobacterium; Data; Development; Drug Design; Evaluation; Evolution; FDA approved; Goals; Growth; Hodgkin Disease; Hybrids; In Vitro; Knowledge; Lead; Libraries; Machine Learning; Malignant Neoplasms; Mass Spectrum Analysis; Methods; Modernization; Molecular; Natural Products; Nuclear Magnetic Resonance; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Principal Component Analysis; Process; Property; Protons; Publishing; Reaction; Reporting; Research; Role; Source; Structure; Synthesis Chemistry; Techniques; Technology; Therapeutic; Therapeutic Agents; Tissues; anti-cancer; anticancer activity; base; cancer cell; chemical function; combinatorial chemistry; computational intelligence; computerized tools; cytotoxicity; density; design; drug development; drug discovery; liquid chromatography mass spectrometry; metabolomics; novel therapeutics; pharmacophore; plant fungi; predictive tools; quantum; scaffold; screening; small molecule; small molecule libraries; social; software development; success

PROJECT ABSTRACT Cyanobacteria produce secondary metabolites have been well-documented to possess potent and selective anticancer activity, which has resulted in FDA approval of a cyanobacterial antibody-drug-conjugate (ADC) for the treatment of several Hodgkin lymphomas. Even though this highlights the critical role of natural products in the drug discovery, the novelty of structural scaffolds has largely remained steady in the last two decades. Therefore, we aim to design and synthesize a pseudo-natural product library inspired by cyanobacterial metabolites with well-described anti-cancer activity to expand their molecular coverage. Our pseudo-natural product library will develop and describe uncharted chemical space that integrates privileged scaffolds while employing medicinal chemistry approaches, such as combinatorial chemistry and parallel synthesis. We will qualitatively and quantitatively characterize our library using modern computational, machine learning and metabolomic techniques, to compare it with natural products and FDA-approved drugs. The long-term goal of this research is to generate a chemical library rich in natural product scaffolds that are biased towards cancer tissue for drug discovery and development. Our main hypothesis is that our library will contain chemical architectures embedded with biological properties of privileged cyanobacterial structures that describe new chemical space.

项目摘要 蓝藻产生的次生代谢物已经被很好地记录下来 强效和选择性的抗癌活性，这导致FDA批准了一种 蓝藻抗体-药物结合物(ADC)治疗几种霍奇金 淋巴瘤。尽管这突显了天然产品在药物中的关键作用 发现，在过去的两年中，结构支架的新颖性基本保持稳定 几十年。因此，我们的目标是设计和合成一个伪天然产品库 受蓝藻代谢产物的启发，具有良好的抗癌活性 它们的分子覆盖范围。我们的伪天然产品库将开发和描述 未知的化学空间，整合了特权支架，同时使用了药物 化学方法，如组合化学和平行合成。我们会 使用现代计算技术定性和定量地描述我们的图书馆， 机器学习和新陈代谢技术，将其与天然产品和 FDA批准的药物。这项研究的长期目标是建立一个化学库 富含天然产物支架，偏向于癌症组织用于药物开发 和发展。我们的主要假设是我们的图书馆会有化学物质 嵌入特权蓝藻结构生物学特性的体系结构 描述了新的化学空间。