ANTITUMOR AGENTS: SYNTHESIS OF MITOMYCIN ANALOGS

抗肿瘤剂：丝裂霉素类似物的合成

• 批准号: 3165550
• 负责人: WILLIAM A REMERS
• 金额: $ 12.37万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-09-15 至 1987-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165550
• 关键词: alkylating agents; antineoplastic antibiotics; aziridines; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; malignant ascites; mitomycin C; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; transplantation

Our goal is to develop new mitomycin analogs which are equally potent (dose level) to mitomycin C, but have a superior antitumor effect and cause less leukopenia (the limiting clinical toxicity). These analogs are designed to be consistent with the mitomycin mode of action and structure-activity relationships. New 7-substituted analogs of mitomycin C will be prepared, but emphasis will be on optimizing antitumor activity around three structural types: alkyl thiols and related disulfides, amino acids, and potential chelating agents. Their structures will incorporate features such as secondary and aryl amines that were found to confer high activity in previous analogs. Promising initial studies on metal chelation by mitomycins will be expanded. The structures of chelates will be elucidated with the aid of 13C NMR and UV absorption studies. Polarographic reduction potentials of the chelates will be measured and attempts will be made to correlate them with antitumor activity. The effect of chelation on the production of superoxide and hydroxyl radicals upon reduction and reoxidation of mitomycin analogs will be studied. Among the new potential chelating agents to be synthesized will be series of compounds in which the number and nature of ligands and the ring sizes are varied. An EDTA derivative of mitomycin C, capable of chelating iron, will be prepared. A new type of mitomycin analog will be synthesized and tested. It will combine the structural features of our 1-substituted mitosenes and Anderson's bis(hydroxymethyl)-1H-phyrrolizine biscarbamates. This combination should confer the advantage of bioreductive activation on the good activity of the pyrrolizine biscarbametes. The existing arrangements on antitumor screening and leukopenia determination by Bristol Laboratories and NCI contractors will be maintained.

我们的目标是开发同样有效的新丝裂霉素类似物（剂量 水平）到丝裂霉素C，但具有较高的抗肿瘤作用，并降低 白细胞减少症（有限的临床毒性）。 这些类似物被设计为 与丝裂霉素的作用方式和结构活性一致 关系。 将准备新的7种丝裂霉素C的7个取代类似物，准备 但是重点将是优化三个抗肿瘤活动 结构类型：烷基硫醇和相关二硫化物，氨基酸和 潜在的螯合剂。 他们的结构将包含功能 例如，被发现赋予高活性的次级和芳基胺 在以前的类似物中。 有希望的关于丝裂霉素金属螯合的初步研究将是 扩展。 螯合物的结构将借助 13C NMR和UV吸收研究。 光学减少电势 将测量螯合物，并尝试将它们关联 具有抗肿瘤活性。 螯合对生产的影响 还原和再氧化后，超氧化物和羟基自由基 将研究丝裂霉素类似物。 在新的潜在螯合中 要合成的代理将是一系列数字的化合物 配体的性质和环大小各不相同。 EDTA衍生物的 丝裂霉素C将准备螯合铁。 将合成和测试一种新型的丝裂霉素类似物。 会 结合我们的1个取代Mitosenes的结构特征和 Anderson的BIS（羟甲基）-1H- phyrrolizine biscarbamates。 这 组合应赋予生物学激活的优势在 吡咯氨酸biscarbametes的良好活动。 抗肿瘤筛查和白细胞减少的现有安排 布里斯托尔实验室和NCI承包商的决心将是 维护。