Organogold phosphorus-containing compounds as antitumor agents

有机金含磷化合物作为抗肿瘤剂

• 批准号: 7761457
• 负责人: Maria Contel
• 金额: $ 15.7万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761457
• 关键词: Adverse effects; Affinity; Apoptosis; Apoptotic; Arts; Award; Binding; Biochemical; Biological; Biological Assay; Cancer cell line; Carboplatin; Cell Line; Cells; Cervix carcinoma; Chemicals; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Collaborations; Comparative Study; Complement; Complex; DNA; DNA Damage; Data; Development; Electron Transport Complex III; Enzymes; Evaluation; Funding; Goals; Gold; Gold Compounds; HIV; Health; Hela Cells; Human; In Vitro; Inhibitory Concentration 50; Laboratories; Ligands; Light; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Mission; Mitochondria; Mitochondrial Proteins; New York; Nucleic Acids; Oxidation-Reduction; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorus; Pilot Projects; Platinum; Preparation; Principal Investigator; Property; Public Health; Publishing; Purines; Reporting; Research; Research Personnel; Resistance; Solid; Solid Neoplasm; Structure-Activity Relationship; Synthesis Chemistry; System; Techniques; Testing; Texas; United States National Institutes of Health; Universities; Work; antitumor agent; base; chemotherapy; cytotoxic; cytotoxicity; design; human disease; hydrophilicity; improved; in vivo; innovation; insight; leukemia; lipophilicity; novel; oxaliplatin; oxidation; programs; public health relevance; purine; single molecule; tumor

DESCRIPTION (provided by applicant): An increasing number of reports on the biological activity of gold(I) and gold(III) complexes have brought to light their capacity to act against solid tumors. However, there is a gap in understanding the plausible mechanisms by which gold compounds act as antitumor agents. The long-term goal of this proposal is the development of novel gold-derived anticancer chemotherapeutics that can overcome some of the drawbacks associated with the use of current platinum drugs. Our hypothesis is that by varying the oxidation state and coordination geometry of the gold derivatives we can modulate and improve their activity as anti-tumor agents. These complexes may prove to be effective antitumor agents acting through different mechanisms than those of cisplatin. Some of the effects of existing gold compounds in vitro appear to be a consequence of direct interference with redox-dependent mitochondrial functions (inhibition of mitochondrial enzymes) instead of binding and damaging DNA but mechanistic data is limited. We will synthesize stable gold compounds with different oxidation states and varying ligand coordination geometries. Subsequently, the cytotoxicity profiles and mechanism of action of gold derivatives will be evaluated in different cancer cell lines. Our specific aims are: (1) Synthesis of gold(I) and gold(III) compounds with pincer phosphorus containing ligands, (2) Study of the cytotoxic/apoptotic properties against human cancer cell lines in vitro, stability, and mechanism of action of the gold-derived compounds. This second aim contains three well-defined research objectives: A) In vitro evaluation of the cytotoxicity profiles of the gold derived compounds against selected cell lines. B) Study of the stability of the compounds in vitro by 31P NMR under biologically relevant conditions. C) Elucidation of the mechanism of action of gold derived cytotoxic compounds. The study of the interaction of selected compounds with DNA and mitochondrial proteins will shed light on the possible mechanisms of action of gold compounds with the same set of ligands and in different oxidation states. A systematic study of the effects of gold compounds in different oxidation states on mitochondrial functions will be subsequently undertaken. An extra innovative approach in this application is that the set of ligands chosen to be coordinated to the gold centers allows the preparation of gold compounds in different oxidation states (I and III) as well as the preparation of bimetallic gold complexes. This will allow a comparative study of oxidation state versus biological activity as well as the study of synergist biological effects caused by more than one metallic centre. Thus, the proposed research is relevant to that part of NIH's mission in the cure of human diseases by developing novel pharmaceuticals as possible alternatives to antitumor platinum chemotherapeutics. PUBLIC HEALTH RELEVANCE: The proposed studies are important since they will help to design new anticancer pharmaceuticals by understanding the mechanism of action of gold compounds. This has relevance to public health, because of the clinical problems associated to the drugs currently used. Thus, the findings are ultimately expected to be applicable to the health of human beings.

描述（由申请人提供）：越来越多的关于金（I）和金（III）络合物生物活性的报道揭示了它们对实体瘤的作用能力。然而，在理解金化合物作为抗肿瘤剂的合理机制方面存在差距。该提案的长期目标是开发新的金衍生抗癌化疗药物，可以克服与使用当前铂类药物相关的一些缺点。我们的假设是，通过改变金衍生物的氧化态和配位几何形状，我们可以调节和改善其作为抗肿瘤剂的活性。这些配合物可能被证明是有效的抗肿瘤药物，通过不同的机制比顺铂。现有金化合物在体外的一些作用似乎是直接干扰氧化还原依赖性线粒体功能（抑制线粒体酶）的结果，而不是结合和破坏DNA，但机制数据有限。我们将合成具有不同氧化态和不同配体配位几何构型的稳定的金化合物。随后，将在不同的癌细胞系中评价金衍生物的细胞毒性特征和作用机制。我们的具体目标是：（1）具有钳形含磷配体的金（I）和金（III）化合物的合成。（2）研究金衍生化合物的体外抗人癌细胞系的细胞毒性/凋亡性质、稳定性和作用机制。第二个目标包含三个明确的研究目标：A）金衍生化合物对选定细胞系的细胞毒性特征的体外评价。B）在生物学相关条件下通过31 P NMR研究化合物的体外稳定性。C）阐明金衍生的细胞毒性化合物的作用机制。对选定化合物与DNA和线粒体蛋白质相互作用的研究将揭示具有相同配体和不同氧化态的金化合物的可能作用机制。随后将对不同氧化态的金化合物对线粒体功能的影响进行系统研究。本申请中的一个额外的创新方法是，选择与金中心配位的配体组允许制备不同氧化态（I和III）的金化合物以及制备双金属金络合物。这将允许对氧化态与生物活性进行比较研究，以及研究由一个以上的金属中心引起的生物学效应。因此，拟议中的研究与NIH的使命有关，即通过开发新的药物作为抗肿瘤铂化疗药物的可能替代品来治疗人类疾病。 公共卫生关系：拟议的研究是重要的，因为它们将有助于通过了解金化合物的作用机制来设计新的抗癌药物。这与公共卫生有关，因为与目前使用的药物有关的临床问题。因此，这些发现最终有望适用于人类的健康。