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）配合物生物活性的报告揭示了它们对抗实体肿瘤的能力。然而，在理解金化合物作为抗肿瘤药物的合理机制方面存在差距。该提案的长期目标是开发新型金衍生抗癌化疗药物，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，我们可以调节和提高它们作为抗肿瘤剂的活性。这些复合物可能被证明是有效的抗肿瘤药物，其作用机制与顺铂不同。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的线粒体功能（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位几何形状的稳定金化合物。随后，我们将在不同的癌细胞系中评估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)合成含钳子磷配体的金(I)和金（III）化合物；(2)体外研究金衍生化合物对人类癌细胞的细胞毒/凋亡特性、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)在体外评估金衍生化合物对选定细胞系的细胞毒性谱。B)在生物相关条件下通过31P NMR研究化合物的体外稳定性。C)阐明了金衍生的细胞毒性化合物的作用机制。研究所选化合物与DNA和线粒体蛋白的相互作用，将有助于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。随后将进行不同氧化态金化合物对线粒体功能影响的系统研究。在这个应用中，另一个创新的方法是选择一组与金中心配合的配体，可以制备不同氧化态（I和III）的金化合物，以及制备双金属金配合物。这将允许氧化态与生物活性的比较研究，以及由多个金属中心引起的协同生物效应的研究。因此，拟议的研究与NIH的使命有关，即通过开发新型药物作为抗肿瘤铂类化疗药物的可能替代品来治愈人类疾病。