Synthetic Study on Antitumor Compounds Starting from Carbohydrates

以碳水化合物为原料的抗肿瘤化合物的合成研究

• 批准号: 06680566
• 负责人: CHIDA Noritaka
• 金额: $ 1.41万
• 依托单位: Keio 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: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06680566/
• 关键词: 7-Deoxypanacratistatin; 7-Deoxy-trans-dihydronarciclasine; FR65814; Antitumor compounds; Ferrier's Carbocyclization reaction; Claisen rearrangement; Palladium Catalyzed Cyclization; Carbohydrates; クライゼン転位; パンクラチスタチン; Ferrier反応

The development of new chemotherapeutic agent against cancer prossessing high activity and low toxicity is a highly important task in medical science. The major objective of this research is to establish the synthetic route to the compounds having high anti-tumor activity starting from readily available carbohdyrates.Toward this end, total synthesis of 7-deoxypancratistatin and FR 65814, both are expected to be novel lead compounds for new chemotherapeutic agents against cancer, starting from D-glucose is investigated.1. Total Synthesis of 7-Deoxypancratistatin.7-Deoxypancratistatin and pancratistatin, both are phenanthridone alkaloids, were isolated from the roof of the plant and has been reported to show high activity in several anticancer test systems. Due to their low natural abundance as well as practical complications in separation, the development of synthetic method for these compounds are highly desired. The aminocyclohexane portion of 7-deoxypancratistatin was effectively con … More structed in an optically pure form from D-glucose utilizing ferrier's carbocyclization reaction. After condensation with 6-bromopiperonic acid, the resulting bromo-enamide was converted into phenanthridone by means of Pd-catalyzed cyclization. Stereoselective hydrogenation and introduction of hydroxy group via epoxide afforded 7-deoxypancratistatin. The precursor of 7-deoxypancratistatin was aiso converted into another natural alkaloid, 7-deoxy-trans-dihydronarciclasine. Thus, stereoselective synthetic pathway to 7-deoxpancratistatin starting from D-glucose was established. Further synthetic study toward pancratistatin is underway.2. Synthetic Study of FR65814.FR65814 is a novel immunosuppressant isolated from culture broth of Penicillium. The structural resaemblance of FR 65814 to fumagillol makes this compound promising for anti-tumor agent. For the synthesis FR65814, its highly oxygenated cyclohexane ring was prepared by Ferrier's carbocyclization reaction from D-glucose. After stereoselective reduction of the ketone carbonyl, the side chain of FR 65814 was effectively introduced by Claisen rearrangement. The product was converted into ally alcohol derivative, which is expected to be a potent precursor for the total synthesis of FR 65814. Less

开发高效、低毒的抗癌化疗药物是当今医学界的一项重要课题。本研究的主要目的是建立一条以易得的羧酸为原料合成具有抗肿瘤活性的化合物的路线，并以D-葡萄糖为起始原料，全合成了有望成为新型抗癌药物的先导化合物7-脱氧潘克斯他汀和FR 65814. 7-脱氧潘生丁的全合成。7-脱氧潘生丁和潘生丁都是菲酮生物碱，从植物的屋顶中分离得到，并已报道在几种抗癌试验系统中显示出高活性。由于其天然丰度低以及分离中的实际复杂性，高度期望开发这些化合物的合成方法。对7-脱氧潘生丁的氨基环己烷部分进行了有效的抑制， ...更多信息 利用Ferrier碳环化反应由D-葡萄糖以光学纯的形式结构化。在与6-溴胡椒酸缩合后，通过Pd催化的环化将所得的溴-烯酰胺转化为菲酮。立体选择性氢化和通过环氧化物引入羟基得到7-脱氧潘克拉司他汀。7-deoxypancratistatin的前体也被转化为另一种天然生物碱7-deoxy-trans-dihydronarciclasine。因此，建立了以D-葡萄糖为起始原料立体选择性合成7-脱氧潘生丁的合成路线。目前正在对泮曲他汀进行进一步的合成研究. FR 65814的合成研究FR 65814是从青霉菌发酵液中分离得到的一种新型免疫抑制剂。FR 65814对烟曲霉醇的结构改造使其有望成为抗肿瘤药物。对于FR 65814的合成，其高度氧化的环己烷环通过Ferrier碳环化反应从D-葡萄糖制备。在酮羰基的立体选择性还原之后，FR 65814的侧链通过Claisen重排有效地引入。产物转化为烯丙醇衍生物，有望成为FR 65814全合成的有效前体。少

项目成果

千田憲孝: "アルドヘキソース類を出発原料としたシクロヘキサンユニットを有する天然物の合成" 有機合成化学協会誌. 53. 858-868 (1995)

Noritaka Senda：“使用己醛糖作为起始原料合成含有环己烷单元的天然产物”有机合成化学学会杂志 53. 858-868 (1995)。

N.Chida and S.Ogawa: "Synthesis of Natural Products Containing Cyclohexane Units Starting from Aldohexoses" Journal of Synthetic Organic Chemistry, Japan. 53. 858-868 (1995)

N.Chida 和 S.Okawa：“从己醛糖开始合成含有环己烷单元的天然产物”，合成有机化学杂志，日本。