Development of Stabilized Zampanolide Mimics as Chemotherapeutics for Prostate Cancer

开发稳定的 Zampanolide 模拟物作为前列腺癌化疗药物

• 批准号: 9765333
• 负责人: QiaoHong Chen
• 金额: $ 14万
• 依托单位: CALIFORNIA STATE UNIVERSITY FRESNO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765333
• 关键词: American; Award; Binding; Binding Sites; Biological Assay; Biological Availability; Caco-2 Cells; Cell Proliferation; Cells; Chemicals; Clinical; Clinical Treatment; Collaborations; Cytotoxic agent; Data; Development; Drug Kinetics; Drug effect disorder; Drug-sensitive; Dyes; Exclusion; Family; Funding Opportunities; Future; Grant; Hepatocyte; Human; In Vitro; Incidence; Lactones; Lead; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Mentors; Metabolic; Methods; Microtubule Stabilization; Microtubule stabilizing agent; Microtubules; Modeling; Normal Cell; Permeability; Positioning Attribute; Procedures; Productivity; Protocols documentation; Publishing; Research; Research Proposals; Resistance; Safety; Side; Solubility; Source; Structure; Structure-Activity Relationship; Suspensions; Techniques; Testing; Therapeutic; Toxic effect; Training; Trypan Blue; Tubulin; United States National Institutes of Health; Work; base; castration resistant prostate cancer; cytotoxic; design; docetaxel; drug candidate; drug development; experience; falls; gastrointestinal; graduate student; improved; in vivo; lead series; men; mortality; programs; prostate cancer cell; prostate cancer cell line; public health relevance; undergraduate student

Project Summary Abstract: Approximately 30,000 American men die each year of metastatic castration-resistant prostate cancer (CRPC) due to the inevitable progression of resistance to first-line treatment with Docetaxel. As a unique addition to the family of microtubule-stabilizing cytotoxic agents (MSAs), zampanolide covalently binds to-tubulin, whereas docetaxel binds non-covalently. This has opened up new avenues to more-effective chemotherapeutics for CRPC. However, limited supply of natural zampanolide from the wild constitutes a serious obstacle to support further drug development activities. Four published synthetic approaches are not efficient and CANNOT serve as its alternative source for further development as a drug candidate. More importantly, we envision that zampanolide possesses poor pharmacokinetic profiles as a drug candidate due to its chemically fragile side chain and metabolically vulnerable lactone moiety. The objective of the proposed research is therefore to develop zampanolide mimics to improve their pharmacokinetic profiles, therapeutic window, and synthetic efficiency yet retain the impressive therapeutic potency and unique mechanism of action for potentially clinical treatment of CRPC. The fundamental hypotheses of this project are: 1) that bioisosteric replacements of the N-acyl hemiaminal side chain and of the lactone in core structure of zampanolide will improve their chemically and metabolically stability yet retain the impressive cytotoxic potency as well as the unique mechanism of action; and 2) remodeling the side chain and/or simplification of the core structure will enable the syntheses to be means for a reliable and renewable source of material. The following specific studies will be carried out to test these hypotheses: 1) To establish stabilized mimics of (-)-zampanolide and practical synthetic methods. A group of zampanolide mimics, with N-acyl hemiaminal and lactone moiety remodeled, will be synthesized by practical and manageable methods. The cytotoxic and anti-proliferative potency against both drug-sensitive and resistance prostate cancer cells will be assessed; 2) To identify simplified and stabilized mimics as well as manageable synthetic methods. A group of new stabilized zampanolide mimics with a simplified core will be synthesized and evaluated; 3) To define the in vitro pharmacokinetic profiles and toxicity of promising mimics; and 4) To validate the covalently-binding mechanism of action as MSAs. This proposal is expected to result in, at least, a new stabilized zampanolide mimic with retained in vitro potency against both drug-sensitive and resistant prostate cancer cells and unique mechanism of action, as well as good in vitro pharmacokinetic and safety profiles. This proposal will bring to my research group with techniques in in vitro pharmacokinetic and mechanistic studies of drug actions and allow me to bring high quality research experiences to the undergraduate and graduate students, and position me to be competitive for SC1, R15, R01, and other NIH awards in the future.

项目摘要摘要： 每年大约有30,000名美国男性死于转移性cast割前列腺癌（CRPC） 由于不可避免的对多西他赛对一线治疗的抵抗力不可避免。作为独特的补充 微管稳定的细胞毒性剂（MSA）家族，Zampanolide共价结合微管蛋白 多西他赛无共价结合。这为更有效的化学治疗方法开辟了新的途径 CRPC。但是，野生宪法中天然Zampanolide的供应有限，这是一个严重的支持障碍 进一步的药物开发活动。四种已发表的合成方法不是有效的，不能服务 作为作为候选药物进一步发展的替代来源。更重要的是，我们设想 Zampanolide由于其化学脆弱的侧 链和代谢脆弱的内酯部分。因此，拟议研究的目的是 开发Zampanolide Mimics以改善其药代动力学特征，治疗窗口和合成 效率却保留了令人印象深刻的治疗效力和独特的作用机理，以实现潜在的临床 CRPC的处理。该项目的基本假设是：1） Zampanolide的核心结构中的N-酰基半乳糖侧链和内酯的侧链将改善其 化学和代谢稳定性，但保留了令人印象深刻的细胞毒性效力以及独特的 作用机理； 2）重塑侧链和/或简化核心结构将 使合成材料可以作为可靠且可再生的材料来源。以下特定 将进行研究以检验这些假设：1）建立（ - ） - Zampanolide和 实用的合成方法。一组Zampanolide模拟物，带有N-酰基半胺和内酯部分 经过改建，将通过实用且易于管理的方法合成。细胞毒性和抗增殖 将评估针对药物敏感和耐药性前列腺癌细胞的效力； 2）识别 简化和稳定的模拟物以及可管理的合成方法。一组新的稳定 Zampanolide模仿具有简化核心的模拟物将合成和评估； 3）定义体外 有望模仿的药代动力学特征和毒性； 4）验证共价结合机制 作为MSA的行动。预计该建议至少会导致新的稳定Zampanolide Mimic与 保留对药物敏感和抗性前列腺癌细胞和独特机制的体外效力 作用，以及良好的体外药代动力学和安全概况。 该提议将通过体外药代动力学和机械性技术将我的研究小组带给我的研究小组 研究毒品行动，并让我为本科生带来高质量的研究经验 研究生，并将我定位为SC1，R15，R01和其他NIH奖项的竞争力。