Design, Synthesis, and Evaluation of ant-Glioblastoma Agents

抗胶质母细胞瘤药物的设计、合成和评估

• 批准号: 10647664
• 负责人: Paul E Floreancig
• 金额: $ 28.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10647664
• 关键词: Acids; Address; Algae; Alkenes; Alkylating Agents; Alkynes; Ants; Architecture; Biological; Biological Assay; Biology; Blood - brain barrier anatomy; Brain; Cancer cell line; Carbon; Case Study; Cell Line; Cells; Cessation of life; Chemicals; Chemistry; Collaborations; Complex; Coupling; Cyclization; Cytotoxin; Diels Alder reaction; Disease; Environment; Ethers; Evaluation; Exhibits; Generations; Geometry; Glioblastoma; Glioma; Growth; Hydrogen Bonding; Hydrogen Peroxide; Investigation; Lead; Length; Lethal Dose 50; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Methyl Ethers; Modeling; Molecular; Molecular Weight; Natural Products; Natural Source; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Operative Surgical Procedures; Pathway interactions; Pharmacologic Substance; Preparation; Proteomics; Protocols documentation; Radiation therapy; Reaction; Reporting; Route; Structure; Structure-Activity Relationship; Survival Rate; Time; Universities; Work; aggressive therapy; analog; anomer; assay development; chemical synthesis; chemotherapy; cycloaddition; cytotoxic; design; flexibility; functional group; novel strategies; novel therapeutics; prevent; professor; screening; tumor

Project Summary The objective of this submission is to develop the recently isolated natural product neaumycin B into a lead for glioblastoma therapy. Neaumycin B is highly toxic to glioblastoma cells while being significantly less toxic toward other cell lines, suggesting the potential for a unique biological target. The lethality of glioblastomas and the limited options for their treatment provide ample justification to explore and advance new hits. Hits can also serve as the basis for identifying new biological targets that will allow for new assay development for screening additional structures that could show anti-glioblastoma activity. The supply of neaumycin B is limited due to its instability during the prolonged cultivation period. The first Specific Aim, therefore is to develop an efficient, modular synthesis of neaumycin B that will provide suitable quantities for subsequent biological studies and will be sufficiently flexible to be applicable to analog synthesis. The second Specific Aim is to prepare several analogs that address limitations in the advancement of neaumycin B as a lead in glioblastoma therapy. These include accessibility, which will be addressed by synthesizing simplified analogs, and stability, which will be addressed through replacing a conjugated triene unit with stable isosteres. The capacity to prepare chimeric structures through cycloaddition chemistry will be advanced by preparing alkyne-containing analogs. All analogs will be evaluated for their potency toward U87 glioblastoma cells and other cancer cell lines to establish a structure- activity relationship, to validate the observed cell line selectivity, and to guide the preparation of agents for identifying the biological target. The proteomics-based approach to identifying the biological target will facilitate assay development, which will facilitate screening studies for identifying new anti-glioblastoma hits. Specific Aim 3 is directed toward using the microenvironment around a glioma or in a neurodegenerative disease to release a biological effector from a blood-brain barrier transporter. This will allow for localization of the agent in the brain since the release from the transporter will prevent the agents from efflux through the blood-brain barrier. This synthesis-intensive project will involve contributions from experts in chemical biology and proteomics to deliver new approaches for treating glioblastomas and other neurological conditions.

项目摘要 本意见书的目的是将最近分离的天然产品新霉素B开发成一种用于 胶质母细胞瘤治疗。新霉素B对胶质母细胞瘤细胞具有高度毒性，而对胶质母细胞瘤细胞的毒性显著降低 其他细胞系，这表明有可能成为一个独特的生物靶点。胶质母细胞瘤的致命性和 有限的治疗选择为探索和推进新的热门药物提供了充分的理由。点击率也可以 作为识别新的生物靶点的基础，这将允许开发新的筛查分析方法 其他可能显示出抗胶质母细胞瘤活性的结构。新霉素B的供应受到限制，因为它 在延长的养殖期内不稳定。因此，第一个具体目标是开发一种高效的、 新霉素B的模块化合成，将为后续的生物学研究提供合适的数量，并将 具有足够的灵活性，适用于模拟合成。第二个具体目标是准备几个类似物 这解决了新霉素B作为胶质母细胞瘤治疗先导的进展中的局限性。这些措施包括 可访问性，这将通过合成简化的类比来解决；以及稳定性，这将被解决 通过用稳定的同位素体取代共轭的三烯单元。制备嵌合结构的能力 通过环加成反应，合成含炔的类似物将推动化学的发展。所有的类比都将是 评估其对U87胶质母细胞瘤细胞和其他癌细胞株的效力，以建立一种结构- 活性关系，以验证观察到的细胞系的选择性，并指导药物的制备 识别生物目标。基于蛋白质组学的识别生物靶标的方法将有助于 测试开发，这将促进筛选研究，以确定新的抗胶质母细胞瘤药物。特定目标 3是针对利用神经胶质瘤或神经退行性疾病周围的微环境来释放 血脑屏障转运体的生物效应器。这将允许毒剂在大脑中的定位 因为从转运体的释放将阻止药物通过血脑屏障外流。这 合成密集型项目将涉及化学生物学和蛋白质组学专家的贡献，以交付 治疗胶质母细胞瘤和其他神经疾病的新方法。