Hybrid Molecules From Benzylguanidine and Cytotoxic Drugs (Busulfan, Melphalan, Thiotepa) for Specific Therapy of Neuroblastoma

苄基胍和细胞毒性药物（白消安、美法仑、噻替派）的混合分子用于神经母细胞瘤的特异性治疗

• 批准号: 281453513
• 负责人: Professor Dr. Reinhard Brückner
• 金额: --
• 依托单位: Institut für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/281453513?language=en
• 关键词: Hybrid; Molecules; Benzylguanidine; Cytotoxic; Drugs

Around the world, iodine-123 labeled meta-iodobenzylguanidine ([123I]-mIBG) is used for the scintigraphic diagnosis of neuroblastoma. The isotopologe [131I]-mIBG is a routine therapeutical for the same disease. These are culmination points of developments in the sequel of the first respective clinical successes with neuroblastoma in Heidelberg and Tübingen (independent and simultaneous in 1984). Interestingly, non-radioactive [127I]-mIBG reveals anti-neuroblastoma activity, too (and the MYC-associated tumor-specific glucose metabolism plays an important role). The same activity would be exhibited by the para isomer [127I]-pIBG, but its rapid deiodination in the body prevents its clinical application. This joint project of a clinical and a synthetic research plans to endow analogs of mIBG und pIBG, which shall be iodine-free for the first time, with a therapeutic potential for neuroblastoma.We design these analogs as hybrid structures of the iodine-deprived IBG scaffold and of the alkylating moieties of pertinent cytostatics. The structural motive benzylguanidine (BG) shall allow our analogs (BG-drug candidates) to enter neuroblastoma cells via the noradrenalin transporter. The alkylating moieties are inspired by busulfan, mel¬phalanx, and thiotepa. Busulfan and melphalan were selected specifically because they are superior to other cytostatic drugs in conditioning before stem-cell transplantation in neuroblastoma. Accordingly, it may be expected that their incorporation assures an appropriate cytotoxicity. The goal of our 3-year collaborative research plan is to use this design for pairing cell selectivity with cell toxicity in such putative anti-neuroblastoma compounds. Freiburg will synthesize 42 BG-drug candidates and 6 [14C]-labeled isotopologs thereof. This volume of work is realistic due to our unprecedented concept of abolishing iodine from whatever target molecule: this reduces the step requirement by 50%. Tübingen will test all BG-drug candidates. A basic screening will include proliferation/vitality studies and comparisons with busulfan, melphalan, thiotepa, and unlabeled mIBG. Moreover, cell culture assays shall reveal, by which mechanism and to which extent these compounds are taken up by neuroblastoma cells and whether they cause an accumulation in mitochondria. The impact of BG-drug candidates on the metabolism of neuroblastoma cells shall be analyzed at the beginning of an advanced screening. One focus will be on the tumor (neuroblastoma) specific glucose metabolism (Warburg effect) including BG effects on N-myc expression. Another focus will be on DNA damage by the alkylating moieties. The most promising BG-drug candidates at this point of our study shall be analyzed using a neuroblastoma spheroid model. A still more restricted selection of compounds shall be tested on a neuroblastoma-bearing mouse model for identifying the most suitable BG-drug candidate(s) for a potential application in human patients.

在世界范围内，碘-123标记的间碘苄胍（[123 I]-mIBG）用于神经母细胞瘤的放射性诊断。同位素[131 I]-mIBG是治疗相同疾病的常规药物。这些是海德堡和图宾根神经母细胞瘤（1984年独立和同时）首次临床成功的后续发展的高潮点。有趣的是，非放射性[127 I]-mIBG也显示出抗神经母细胞瘤活性（MYC相关的肿瘤特异性葡萄糖代谢起着重要作用）。帕拉异构体[127 I]-pIBG也表现出相同的活性，但其在体内的快速脱碘作用阻碍了其临床应用。这个临床和合成研究的联合项目计划赋予mIBG和pIBG的类似物，这将是第一次无碘，具有治疗神经母细胞瘤的潜力。我们设计这些类似物作为碘剥夺IBG支架和相关细胞抑制剂的烷基化部分的混合结构。结构动力苄基胍（BG）将允许我们的类似物（BG-候选药物）通过去甲肾上腺素转运蛋白进入神经母细胞瘤细胞。烷基化部分受到白消安、美法仑和噻替派的启发。白消安和美法仑被特别选择，因为它们在神经母细胞瘤干细胞移植前的预处理中优于其他细胞抑制药物上级。因此，可以预期它们的掺入确保适当的细胞毒性。我们的3年合作研究计划的目标是使用这种设计，在这种假定的抗神经母细胞瘤化合物中将细胞选择性与细胞毒性配对。弗赖堡将合成42种BG-药物候选物及其6种[14 C]-标记的同位素。这一工作量是现实的，因为我们前所未有的概念，消除碘从任何目标分子：这减少了50%的步骤要求。Tübingen将测试所有BG候选药物。基本筛选将包括增殖/活力研究以及与白消安、美法仑、塞替派和未标记mIBG的比较。此外，细胞培养试验将揭示这些化合物被神经母细胞瘤细胞吸收的机制和程度，以及它们是否引起线粒体中的积累。应在高级筛选开始时分析BG候选药物对神经母细胞瘤细胞代谢的影响。一个重点是肿瘤（神经母细胞瘤）特异性葡萄糖代谢（瓦尔堡效应），包括BG对N-myc表达的影响。另一个重点将是DNA损伤的烷基化部分。在我们的研究的这一点上，最有希望的BG-药物候选物将使用神经母细胞瘤球体模型进行分析。应在携带神经母细胞瘤的小鼠模型上测试更有限的化合物选择，以鉴定用于人类患者的潜在应用的最合适的BG-药物候选物。