Covalent Modification of DNA and Protein by Bioactivated Antitumor Acylfulvenes

生物活性抗肿瘤酰基富烯对 DNA 和蛋白质的共价修饰

• 批准号: 7611449
• 负责人: SHANA J STURLA
• 金额: $ 4.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-23 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611449
• 关键词: Abbreviations; Accounting; Address; Affect; Alkylating Agents; Alkylation; Antineoplastic Agents; Apoptosis; Binding; Biochemical Process; Biological; Biological Factors; Biological Process; Buffers; Cell Death; Cells; Chemical Structure; Chemicals; Class; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Complex; Coupled; DNA; DNA Adducts; DNA Alkylation; DNA Damage; DNA Modification Process; DNA Repair; DNA biosynthesis; DNA chemical synthesis; Data; Development; Disruption; Dose-Limiting; Engineering; Environment; Enzyme Inhibition; Enzymes; Event; Future; Genetic Transcription; Goals; In Vitro; Investigation; Knowledge; Lead; Link; Maps; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Methodology; Methods; Modeling; Modification; Molecular Probes; Nature; Nucleosides; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Pattern; Pharmaceutical Preparations; Principal Investigator; Process; Proteins; Publishing; Reaction; Reactive Oxygen Species; Reagent; Reporting; Research; Research Design; Resistance; Role; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Structure; System; TP53 gene; Testing; Therapeutic Index; Thioredoxin; Toxic effect; Tumor Cell Line; Work; acylfulvene; adduct; analog; analytical method; analytical tool; base; cancer cell; cancer therapy; cellular engineering; cellular targeting; chemical carcinogenesis; chemical synthesis; chemotherapeutic agent; cytotoxicity; design; diene; drug sensitivity; enzyme activity; illudin M; improved; innovation; irofulven; killings; neoplastic cell; nucleobase; small molecule; therapy design; thioredoxin reductase; tool; tumor

Project Summary: Acylfulvenes, derivatives of illudin natural products, are a promising class of drugs for cancer treatment. They are notable for high therapeutic indices and selectivitiesfor tumor cells, and clinical trials are underway. Acylfulvenes are alkylating agents, but the detailed chemical mechanisms of DNA and protein-adduct formation, and how this relates to tumor-cell selectivity is not known. The long-term goals of this project are to define a mechanistic paradigm accounting for the selectivetoxicities of acylfulvenes that will lead to the development of combined-agent and tailored therapies designed to site-specifically tune acylfulvene toxicity. The objectivesof this application are to establish a link from acylfulvene bioactivation to biomolecular target modification and cytotoxicity. The specific aims are to (1) Characterize in vitro patterns of DNA alkylation by acylfulvenes and distinguish adducts that result from direct modification of DNA from those of bioactivation- coupled reactions; (2) Characterize the mechanism of inhibition of cellular redox proteins by acylfulvenes; (3) Determine the Influence of a bioactivating reductase on acylfulvene alkylation reactions and toxicity in cells. The research approach for aim 1 involves the synthesis of chemically activated molecular probes that will be used to identify products of DNA alkylation by bioactivatedacylfulvenes. We will use chemical characterization methods to identify the structures of acylfulvene DNA adducts. In aim 2, we will use enzyme-inhibition studies combined with a mass-spectrometry-based approach to structurally map protein covalent modification. In aim 3, we will use reductase-overexpressingcells and stable tumor cell lines to test the impact of adduct formation in the complex environment of the cell. Relevance: Acylfulvenes are a new class of drugs that kill cancer cells by becoming covalently linked to biomolecules in the cell and initiating a sequence of biological events that result in cell death. The initial chemical transformations that govern this process and how they differ in cells that are sensitive to acylfulvenes versus those that are not are unknown. The ability to selectivelytarget tumor cells is a central problem in cancer therapy and consequently understanding this mechanism is important for designing safer cancer therapy strategies.

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