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
基本信息
- 批准号:7496683
- 负责人:
- 金额:$ 2.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AbbreviationsAccountingAddressAffectAlkylating AgentsAlkylationAntineoplastic AgentsApoptosisBindingBiochemical ProcessBiologicalBiological FactorsBiological ProcessBuffersCell DeathCellsChemical StructureChemicalsClassClinicalClinical ResearchClinical TrialsCombined Modality TherapyComplexCoupledDNADNA AdductsDNA AlkylationDNA DamageDNA Modification ProcessDNA RepairDNA biosynthesisDNA chemical synthesisDataDevelopmentDisruptionDose-LimitingEngineeringEnvironmentEnzyme InhibitionEnzymesEventFutureGenetic TranscriptionGoalsIn VitroInvestigationKnowledgeLeadLinkMapsMass Spectrum AnalysisMediatingMetabolicMetabolismMethodologyMethodsModelingModificationMolecular ProbesNatureNucleosidesOxidation-ReductionOxidoreductasePathway interactionsPatternPharmaceutical PreparationsPrincipal InvestigatorProcessProteinsPublishingReactionReactive Oxygen SpeciesReagentReportingResearchResearch DesignResistanceRoleSignal PathwaySignal TransductionSiteSite-Directed MutagenesisStructureSystemTP53 geneTestingTherapeutic IndexThioredoxinToxic effectTumor Cell LineWorkacylfulveneadductanaloganalytical toolbasecancer cellcancer therapycellular engineeringcellular targetingchemical carcinogenesischemical synthesischemotherapeutic agentcytotoxicitydesigndienedrug sensitivityenzyme activityilludin Mimprovedinnovationirofulvenkillingsneoplastic cellnucleobasesmall moleculetherapy designthioredoxin reductasetumor
项目摘要
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.
项目概要:
酰基富烯类化合物是伊鲁定天然产物的衍生物,是一类很有前途的抗癌药物。
它们以高治疗指数和对肿瘤细胞的选择性而闻名,临床试验正在进行中。
酰基富烯是烷基化试剂,但DNA和蛋白质加合物的详细化学机制
形成,以及这与肿瘤细胞选择性的关系尚不清楚。该项目的长期目标是
定义一种机制范式,解释酰基富烯的选择性毒性,
开发联合药物和定制疗法,旨在位点特异性调节酰基富烯毒性。
该应用的目标是建立从酰基富烯生物活化到生物分子靶点的联系
修饰和细胞毒性。具体目的是(1)通过以下方法表征DNA烷基化的体外模式:
酰基富烯和区别加合物,从生物活化的DNA直接修饰的结果-
偶联反应;(2)表征酰基富烯抑制细胞氧化还原蛋白的机制;(3)
测定生物活化还原酶对细胞中酰基富烯烷基化反应和毒性的影响。
aim 1的研究方法包括合成化学活化的分子探针,
用于鉴定生物活性酰基富烯的DNA烷基化产物。我们将使用化学
表征方法来鉴定酰基富烯DNA加合物的结构。在目标2中,我们将使用
酶抑制研究结合基于质谱法的蛋白质结构图谱方法
共价修饰在aim 3中,我们将使用还原酶过表达细胞和稳定的肿瘤细胞系来测试
加合物形成在细胞复杂环境中的影响。
相关性:
酰基富烯是一类新型药物,通过与生物分子共价连接来杀死癌细胞,
并引发导致细胞死亡的一系列生物事件。初始化学
控制这一过程的转化,以及它们在对酰基富烯敏感的细胞与对酰基富烯敏感的细胞中的差异。
那些没有的是未知的。选择性靶向肿瘤细胞的能力是癌症的核心问题
因此,了解这种机制对于设计更安全的癌症治疗方法非常重要
战略布局
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('SHANA J STURLA', 18)}}的其他基金
238th American Chemical Society National Meeting
第 238 届美国化学会全国会议
- 批准号:
7749286 - 财政年份:2009
- 资助金额:
$ 2.81万 - 项目类别:
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:
7259793 - 财政年份:2007
- 资助金额:
$ 2.81万 - 项目类别:
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 - 财政年份:2007
- 资助金额:
$ 2.81万 - 项目类别:
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:
7778843 - 财政年份:2007
- 资助金额:
$ 2.81万 - 项目类别:
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:
8101215 - 财政年份:2007
- 资助金额:
$ 2.81万 - 项目类别:
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:
7409710 - 财政年份:2007
- 资助金额:
$ 2.81万 - 项目类别:
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:
7612044 - 财政年份:2007
- 资助金额:
$ 2.81万 - 项目类别:
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