MITOMYCIN SYNTHESIS AND NITRONE-BASED METHODOLOGY

丝裂霉素的合成和硝基方法

• 批准号: 3165301
• 负责人: ROBERT M. COATES
• 金额: $ 10.83万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-04-01 至 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165301
• 关键词: N hydroxylation; antineoplastic antibiotics; antineoplastics; chemical structure function; cyclic amine; drug design /synthesis /production; hydroxamate; hydroxylamine; mitomycin C; nitrone

The utility of mitomycin C in cancer chemotherapy has been limited by its toxic side effects. One objective of this research is to develop an efficient synthesis of 1,2-aziridino mitosenes by use of the modified Nenitzescu reaction. The presence of the aziridine ring is essential for high anti-tumor activity and this synthetic approach should open the way for synthesis of a new family of modified aziridino mitosenes differing at C-6. Another aspect of this project is the development of new methodology for diastereo- and enantioselective synthesis of amines, amino alcohols, and other multiply functionalized amino compounds by addition of carbon nucleophiles to nitrones. The stereoelectronic factors and the effects of chelating groups on the C- and N-substituents on the stereoselectivity of nitrone additions will be evaluated. New methods for synthesis of Alpha,Beta-aziridino esters and Beta-lactams via nitrone additions are proposed. A stereoselect-synthesis of L-acosamine, the sugar component of 4'-epi-adriamycin, a promising antitumor agent, and of a thienomycin model compound are outlined to demonstrate the utility of these methods. A family of cyclic and acyclic thioimidate and thiocarbamimidate N-oxides, novel nitrones of thio esters and thio carbonates, are to be synthesized. Inter- and intramolecular cycloadditions as well as acylation-rearrangement reactions of these carboxylate nitrones will be carried out.

丝裂霉素C在癌症化学疗法中的效用受到其限制 有毒的副作用。 这项研究的一个目的是开发 通过使用改良的 nenitzescu反应。 氮杂氨酸环的存在对于 高抗肿瘤活性和这种合成方法应打开道路 为了综合一个新的修改的阿齐里迪诺群岛，在 C-6。 该项目的另一个方面是开发新方法 胺，氨基醇和对映选择性合成和对映选择性合成 通过添加碳的其他乘积化氨基化合物 亲核试剂到硝基。 立体电子因素和 在立体选择性的C-和N-靠近基质上的螯合基团的立体选择性 硝基添加将进行评估。 合成的新方法 通过硝基添加的Alpha，beta-aziridino酯和β-内酰胺酯是 建议的。 L- acosamine的立体选择合成，糖成分的糖成分 4'-epi-adrimycin，一种有前途的抗肿瘤剂和硫霉素模型 概述了化合物以证明这些方法的实用性。 循环和无环硫代象征和硫代氨基酰胺酰胺的n-氧化物的家族， 要合成硫酯和硫代碳酸盐的新氮。 分子内和分子内环加成以及酰基化的重态 这些羧酸盐的反应将进行。