Creation of novel antitumor agents having DNA topoisomerase inhibition activity

具有DNA拓扑异构酶抑制活性的新型抗肿瘤药物的研制

• 批准号: 11680591
• 负责人: IWAO Masatomo
• 金额: $ 2.37万
• 依托单位: Nagasaki university
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680591/
• 关键词: marine natural products; pyrroloiminoquinone; anticancer agent; topoisomerase inhibition; トポイソメラーゼ; リチオ化反応

Pyrroloiminoquinone marine alkaloids exhibit antitumor activity through DNA topoisomerase inhibition.Consequently, these alkaloids have attracted considerable attention as new leads of antitumor agent. Although several methods to construct pyrroloiminoquinone skeleton have been developed so far, no method to introduce substituents on the desirable position has been establislted.Previously, we have developed a novel strategy to build up the pyrroloiminoquinone core, and achieved the total synthesis of makaluvamined A, D, I and K.Following this study, we have now establised an efficient method to bind a variety of substituents at the C-6 position of the pyrroloiminoquinone core via regioselective lithiation of 5-Boc-TIPS-7-methoxy-1,3,4,5-tetrahydropyrrolo [4,3,2-de] quinoline, which was readily prepared from a key intermediatein the makaluvamine synthesis. This method was successfully applied to the first total synthesis of veiutamine, a new type of pyrroloiminoquinone marine alkaloid having p-hydroxybenzyl group at C-6.In addition, we have developed C-6 and C-2 selective lithiation of 5-Boc-7-methoxy-1-methyl-1,3,4,5- tetrahydropyrrolo [4,3,2-de] quinoline and synthesized a number of its derivatives. In conclusion, we believe these methods developed in this study enable to produce a variety of pyrroloiminoquinone marine alkaloids and their analogues. The subsequent structure-activity relationship studies of these compounds would allow to create a new type of anticancer agent.

吡咯亚氨基醌类海洋生物碱通过抑制DNA拓扑异构酶而显示出抗肿瘤活性，因此，这些生物碱作为新的抗肿瘤药物的先导受到了广泛的关注。虽然到目前为止已经开发了多种方法来构建吡咯亚氨基醌骨架，但还没有建立在理想位置引入取代基的方法。在此之前，我们开发了一种新的方法来构建吡咯亚氨基醌核心，并实现了Makaluvamine A，D，I和K的全合成。在本研究之后，我们建立了一种有效的方法，通过区域选择性地将5-Boc-TIPS-7-methoxy-1，3，4，5-tetrahydropyrrolo[4，3，2-De]喹啉连接到吡咯亚氨基醌核心的C-6位上，该方法很容易从Makalvamine合成的关键中间体中制备出来。该方法首次成功地用于维乌他明的全合成，这是一种新型的C-6位含对羟基苯基的吡咯亚氨基海洋生物碱。此外，我们还研究了5-Boc-7-甲氧基-1-甲基-1，3，4，5-四氢吡咯并[4，3，2-de]喹啉的C-6和C-2选择性锂化反应，并合成了一系列的衍生物。综上所述，我们相信本研究开发的这些方法可以生产多种吡咯亚氨基醌海洋生物碱及其类似物。后续对这些化合物的构效关系研究将可能创造出一种新型的抗癌药物。

项目成果

Y.Moro-oka,S.Iwakiri,T.Fukuda,M.Iwao: "Remarkable effect of water in a regioselective lithiation of 5-(tert-butoxycarbonyl)-7-methoxy-1-methyl-1, 3, 4, 5-tetrahydro [4, 3, 2-de] quinoline"Tetrahedron Letters. 41・6. 5225-5228 (2000)

Y.Moro-oka、S.Iwakiri、T.Fukuda、M.Iwao：“水在 5-(叔丁氧基羰基)-7-甲氧基-1-甲基-1, 3, 4, 区域选择性锂化中的显着效果， 5-四氢[4,3,2-de]喹啉”四面体字母. 41・6. 5225-5228 (2000)

Y.Moro-oka, T.Fukuda, M.Iwao: "The first total synthesis of Veiutamine, a new type of pyrroloiminoquinone marine alkaloid"Tetrahedron Letters. 40(9). 1713-1716 (1999)

Y.Moro-oka、T.Fukuda、M.Iwao：“首次全合成新型吡咯亚氨基醌海洋生物碱 Veiutamine”Tetrahedron Letters。

Y.Moro-oka,T.Fukuda,M.Iwao: "The first total synthesis of Veiutamine, a new type of pyrroloiminoquinone marine alkaloid"Tetrahedron Letters. 40・9. 1713-1716 (1999)

Y.Moro-oka、T.Fukuda、M.Iwao：“新型吡咯亚氨基醌海洋生物碱 Veiutamine 的首次全合成”Tetrahedron Letters 40・9 (1999)。

Y.Moro-oka,S.Iwakiri,T.Fukuda,M.Iwao: "Remarkable effect of water in a regioselective lithiation of 5-(tert-butoxycarbonyl)-7-methoxy-1-methyl-1,3,4,5-tetrahydro[4,3,2-de]quinoline"Tetrahedron Letters. 41・6. 5225-5228 (2000)

Y.Moro-oka、S.Iwakiri、T.Fukuda、M.Iwao：“水在 5-(叔丁氧基羰基)-7-甲氧基-1-甲基-1,3,4 的区域选择性锂化中具有显着效果， 5-四氢[4,3,2-de]喹啉"四面体字母. 41・6. 5225-5228 (2000)

Y.Moro-oka, S.Iwakiri, T.Fukuda, M.Iwao: "Remarkable effect of water in a regioselective lithiation of 5-(tert-butoxycarbonyl)-7-methoxy-1-methyl-1, 3, 4, 5-tetrahydro [4, 3 , 2-de] quinoline"Tetrahedron Letters. 41(6). 5225-5228 (2000)

Y.Moro-oka、S.Iwakiri、T.Fukuda、M.Iwao：“水在 5-(叔丁氧基羰基)-7-甲氧基-1-甲基-1, 3, 4, 区域选择性锂化中的显着效果，