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Synthesis and Study of Natural and Non-natural Antiproliferative Agents

天然和非天然抗增殖剂的合成与研究

基本信息

批准号：
9028591
负责人：
ANDREW G MYERS
金额：
$ 73.88万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-04-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9028591
关键词：
Acute Address Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antibiotics Antibody-drug conjugates Antigens Binding Sites Biological Biological Process Biology CD22 gene Cell Line Cells Chemicals Chemotherapy-Oncologic Procedure Clinic Clinical Collaborations Collection Complex Cytotoxic agent DNA Development Drug Kinetics ERBB2 gene Enzymes Evaluation Exhibits Family Fermentation Funding Goals Growth Health Human In Vitro Inflammation Intervention Investigation Laboratories Lead Malignant Neoplasms Mediating Methods Modification Molecular Molecular Mechanisms of Action Molecular Profiling Molecular Target Myelogenous NPM1 gene Natural Products Norway Oncogenes Phenols Play Production Property Protein Isoforms Protein p53 Proteins Research Ribosomes Route Structure TP53 gene Technology Tetracyclines Therapeutic Therapeutic Intervention Universities Ursidae Family Work Xenograft procedure analog anticancer research antiproliferative agents cancer cell cancer therapy cellular targeting chemical stability chemotherapeutic agent clinically relevant cytotoxic design drug discovery ds-DNA exportin 1 protein functional group improved in vivo in vivo Model innovation leukemia novel nucleophosmin small molecule stephacidin B success systemic toxicity targeted treatment therapeutic development therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Our laboratory is focused on the development of practical synthetic routes to structurally complex natural products that have been shown to inhibit the growth of human cancer cells. Through the use of highly efficient, modular strategies, we are able to prepare large numbers of related structures (analogs) for evaluation as new chemotherapeutic agents, with potentially improved therapeutic or pharmacokinetic properties. The synthetic routes we are developing also allow us to prepare chemical probes that are useful for the identification of the cellular targets of the families of natural products that we study, wich in many cases are unknown. Our research thus aims to address two critical challenges facing the development of novel cancer therapies by both providing new molecules for evaluation as well as elucidating the cellular mechanisms underpinning their biological activities. Indeed, many current front-line small-molecule therapies for cancer are natural products or are derivatives of natural products, and many important cellular targets for therapeutic intervention have been identified through the use of probes prepared by the chemical modification of such molecules. Among the classes of natural products we are studying are the trioxacarcins, bacterial fermentation products with extremely potent inhibitory properties toward growing cancer cells and known to alkylate duplex DNA; avrainvillamides, fungal natural products shown in our laboratory to target nucleophosmin and exportin-1, two proteins known to play key roles in the initiation and progression of acute myelogenous lukemia (AML) and emerging targets for chemotherapeutic intervention; and tetracyclines, bacterial fermentation products initially developed as antibiotics that also exhibit poorly understood anti-cancer and anti-inflammatory activities in human cells.

描述（由申请人提供）：我们的实验室专注于开发结构复杂的天然产物的实用合成路线，这些天然产物已被证明可以抑制人类癌细胞的生长。通过使用高效的模块化策略，我们能够制备大量的相关结构（类似物）作为新的化疗药物进行评估，具有潜在的改善的治疗或药代动力学特性。我们正在开发的合成路线也使我们能够制备化学探针，这些探针可用于识别我们研究的天然产物家族的细胞靶点，在许多情况下，这些天然产物是未知的。因此，我们的研究旨在通过提供新的评估分子以及阐明支撑其生物活性的细胞机制来解决新型癌症疗法开发面临的两个关键挑战。事实上，目前许多用于癌症的一线小分子疗法是天然产物或天然产物的衍生物，并且通过使用通过化学修饰这些分子制备的探针已经鉴定了用于治疗干预的许多重要细胞靶标。在我们正在研究的天然产物类别中，有三恶卡菌素，这是一种细菌发酵产物，对生长的癌细胞具有极强的抑制特性，已知可使双链DNA烷基化; avrainvillamides，我们实验室中显示的靶向核磷蛋白和输出蛋白-1的真菌天然产物，已知在急性髓性白血病（AML）的起始和进展中起关键作用的两种蛋白质和化疗干预的新兴靶点;和四环素类，最初作为抗生素开发的细菌发酵产物，其在人类细胞中也表现出知之甚少的抗癌和抗炎活性。