MITOMYCIN SYNTHESIS AND NITRONE-BASED METHODOLOGY

丝裂霉素的合成和硝基方法

• 批准号: 3165302
• 负责人: ROBERT M. COATES
• 金额: $ 10.81万
• 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 1989-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165302
• 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 在癌症化疗中的应用因其自身的作用而受到限制。 毒副作用。 这项研究的一个目标是开发一种 高效合成 1,2-氮丙啶基核糖体 尼采斯库反应。 氮丙啶环的存在对于 高抗肿瘤活性，这种合成方法应该开辟道路 用于合成修饰的氮丙啶基有丝分裂新家族，其不同之处在于 C-6。 该项目的另一个方面是开发新的方法 胺、氨基醇和的非对映和对映选择性合成 通过添加碳的其他多官能化氨基化合物 亲核试剂为硝酮。 立体电子因素及其影响 C-和N-取代基上的螯合基团对立体选择性的影响 将评估硝酮的添加。 合成新方法 通过硝酮加成得到的 α,β-氮丙啶酯和 β-内酰胺是 建议的。 L-阿考斯胺（L-阿考斯胺）的立体选择合成，L-阿考斯胺是 4'-表阿霉素，一种有前途的抗肿瘤剂，以及噻吩霉素模型 概述了化合物以证明这些方法的实用性。 一族环状和无环硫代亚氨酸酯和硫代氨基甲酰亚胺酯 N-氧化物， 即将合成硫代酯和硫代碳酸酯的新型硝酮。 分子间和分子内环加成以及酰化重排 这些羧酸硝酮的反应将进行。