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.

项目概要 本次提交的目的是将最近分离的天然产物新霉素 B 开发成一种先导药物 胶质母细胞瘤治疗。新霉素 B 对胶质母细胞瘤细胞具有高毒性，而对胶质母细胞瘤细胞的毒性则明显较低 其他细胞系，表明具有独特的生物靶标的潜力。胶质母细胞瘤的致死率和 有限的治疗选择为探索和推进新的治疗方案提供了充分的理由。命中也可以服务 作为确定新生物靶标的基础，从而开发新的筛选分析方法 可以表现出抗胶质母细胞瘤活性的其他结构。新霉素 B 的供应量有限，因为它 长期栽培期间不稳定。因此，第一个具体目标是开发一种高效、 新霉素 B 的模块化合成将为后续生物学研究提供合适的数量，并将 足够灵活以适用于模拟合成。第二个具体目标是制备几种类似物 解决了新霉素 B 作为胶质母细胞瘤治疗先导药物的局限性。这些包括 可访问性（将通过合成简化的类似物来解决）和稳定性（将通过合成简化的类似物来解决） 通过用稳定的电子等排体取代共轭三烯单元。制备嵌合结构的能力 通过环加成化学，将通过制备含炔类似物来推进。所有类似物将是 评估其对 U87 胶质母细胞瘤细胞和其他癌细胞系的效力，以建立结构- 活性关系，验证观察到的细胞系选择性，并指导制剂的制备 确定生物靶标。基于蛋白质组学的方法来识别生物靶标将有助于 检测方法的开发，将有助于筛选研究，以确定新的抗胶质母细胞瘤药物。具体目标 3 旨在利用神经胶质瘤周围或神经退行性疾病周围的微环境来释放 来自血脑屏障转运蛋白的生物效应器。这将允许代理在大脑中定位 因为转运蛋白的释放将阻止药物通过血脑屏障流出。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系统疾病的新方法。