Synthetic studies on Antitumor Antibiotic and Biological Activity

抗肿瘤抗生素及其生物活性的综合研究

• 批准号: 05671865
• 负责人: NAKAGAWA Masako
• 金额: $ 1.34万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05671865/
• 关键词: manzamine A; Diels-Alder Reaction; manzamine C; dynamicin A; Danishefsky's diene; 3-alkyldihydropyridinone; cytotoxicity; azocine

I.Approaches to the total synthesis of manzamineA1. For the challenging construction of the complex hydroisoquinoline framework of manzamine A,we have been investigating a feasibility of the Diels-Alder reaction of suitably protected 3-alkyldihydropyridinones. Through an efficient intrmolecular D-A reaction of the dihydropyridinone and Danishefsky's diene, we have successfully constructed the central tetracyclic core of manzamine A.For the attainment of the more convergent synthetic route, it is preferable use the azocine-containing dienophile. For the preparation of this new dienophile as an optically active form, we investigated the two new synthetic route starting from L-serine derivative.2. According to the computer assisted conformational analysis of manzamine A and C,we have succeeded the synthesis of the natural manzamine C,its trans-isomer, and ring-modified analogs. All of the manzamine C analogs its trans-isomer showed similar in vitro cytotoxic activity to manzamine C itself.II.Approaches to the total synthesis of dynamicine AThe phenanthridine key intermediate for the total synthesis of dynamicin A,a potent antitumor antibiotic, has been synthesized by our synthetic methodology used for manzamine A synthesis.

1.全合成锰胺a1的方法。摘要针对曼扎胺A复杂氢异喹啉骨架的构建挑战，我们研究了适当保护的3-烷基二氢吡啶酮Diels-Alder反应的可行性。通过二氢吡啶酮与丹尼舍夫斯基二烯的分子内D-A反应，我们成功构建了曼扎胺a的中心四环核心。为了获得更收敛的合成路线，最好使用含偶氮嘧啶的亲二酚。为了制备这种具有旋光活性的新型二亲试剂，我们研究了从l -丝氨酸衍生物开始的两种新的合成路线。根据计算机辅助构象分析，我们成功地合成了天然曼扎胺A和C及其反式异构体和环修饰类似物。所有的manzamine C类似物及其反式异构体显示出与manzamine C相似的体外细胞毒活性。ii .动力学A全合成的方法。动力学A是一种有效的抗肿瘤抗生素，用我们用于manzamine A合成的合成方法合成了动力学A全合成的关键中间体phenantithridine。

项目成果

Jian Ma,Masako Nakagawa,Yasuhiro Torisawa and Tohru Hino: "Hydroisoquinoline Ring Construction via The Diels-Alder Reaction of Arecolone-Derived Enol Sily Ethers." Heterocycles. 38. 1609-1618 (1994)

jian Ma、Masako Nakakawa、Yasuhiro Torisawa 和 Tohru Hino：“通过槟榔酮衍生的烯醇硅醚的 Diels-Alder 反应构建氢异喹啉环。”

M.Nakagawa: "Efficient Michael Addition Reactions of the N-Arylsultomyl-3-phenyl-thiepipesidenes.Synthesis of 3-Substituted Dihydropyridinones" Heterocycles. 35. 1157-1170 (1993)

M.Nakakawa：“N-芳基磺酰基-3-苯基-噻哌啶的高效迈克尔加成反应。3-取代的二氢吡啶酮的合成”杂环。

Masako Nakagawa,Yasuhiro Torisawa,et al.: "Dihydropyridinone Approach to Manzamines:An Expedient Construstion of the Tetracyclic Core of Manzamine A." Tetrahedron Lett.34. 4543-4546 (1993)

Masako Nakakawa、Yasuhiro Torisawa 等人：“二氢吡啶酮方法制备曼扎明：曼扎明 A 四环核心的权宜构建”。

Masko Nakagawa, Yasuhiro Torisawa, Toshihiro Hosaka, Kiyoshi Tanabe, Fabric Tavet, Maki Aikawa, and Tohru Hino: "Efficient Michael Addition Reactions of the N-Arylsulfony1-3-Phenylthiopiperidones. Synthesis of 3-Substituted Dihydropyridinones." Heterocycl

Masko Nakakawa、Yasuhiro Torisawa、Toshihiro Hosaka、Kiyoshi Tanabe、Fabric Tavet、Maki Aikawa 和 Tohru Hino：“N-芳基磺酰基 1-3-苯硫哌啶酮的高效迈克尔加成反应。3-取代二氢吡啶酮的合成。”

Masako Nakagawa, Yasuhiro Torisawa, Toshihiro Hosaka, Kiyoshi Tanabe, Tadamase Da-te, Kimio Okamura, and Tohru Hino: "Dihydropyridinone Approach to Manzamines : An Expedient Construction of the Tetracyclic Core of Manzamine A." Tetrahedron Lett.34. 4543-4

Masako Nakakawa、Yasuhiro Torisawa、Toshihiro Hosaka、Kiyoshi Tanabe、Tadamase Da-te、Kimio Okamura 和 Tohru Hino：“Manzamines 的二氢吡啶酮方法：Manzamine A 四环核心的便捷构建”。