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: 10439861
• 负责人: Paul E Floreancig
• 金额: $ 27.8万
• 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/10439861
• 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; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Operative Surgical Procedures; Pathway interactions; Pharmacologic Substance; Preparation; Proteomics; Protocols documentation; Radiation; Reaction; Reporting; Route; Source; Structure; Structure-Activity Relationship; Survival Rate; Time; Universities; Work; aggressive therapy; analog; assay development; base; 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 本申请的目的是将最近分离的天然产物新霉素B开发成用于 胶质母细胞瘤治疗Neaumycin 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显著较低。 其他细胞系，这表明一个独特的生物靶点的潜力。胶质母细胞瘤的致命性和 处理这些问题的办法有限，这就为探索和推动新的成功提供了充分的理由。点击也可以服务于 作为识别新生物靶标的基础，这将允许开发用于筛选的新测定法 可以显示抗胶质母细胞瘤活性的额外结构。新霉素B的供应是有限的， 在长期的栽培过程中，因此，第一个具体目标是制定一个有效的， 新霉素B的模块化合成将为随后的生物学研究提供合适的量， 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 其解决了新霉素B作为胶质母细胞瘤治疗中的先导物的进展的局限性。这些包括 可及性，这将通过合成简化的类似物来解决，和稳定性，这将得到解决 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 通过制备含炔类似物，将促进环加成化学。所有类似物将 评估它们对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，以验证观察到的细胞系选择性，并指导制剂用于 识别生物目标。基于蛋白质组学的方法来识别生物靶标将有助于 分析开发，这将有助于筛选研究，以确定新的抗胶质母细胞瘤命中。具体目标 3是针对使用周围的神经胶质瘤或在神经退行性疾病的微环境， 血脑屏障转运蛋白的生物效应物这将允许在大脑中定位代理 因为从转运蛋白的释放将阻止药剂通过血脑屏障流出。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， 治疗胶质母细胞瘤和其他神经系统疾病的新方法。