Antitumor Antibiotics from Fungi

来自真菌的抗肿瘤抗生素

• 批准号: 01560154
• 负责人: NAKAYAMA Mitsuru
• 金额: $ 1.41万
• 依托单位: Department of Agricultural Chemistry, College of Agriculture, University of Osaka Prefecture
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01560154/
• 关键词: Antitumor antibiotics; Myrocin B; Myrocin C; Pimaran-type antitumor diterpene; Chlorine-containing shikimate; 3ーメトキシー2,5ートルキノン; Myrothecium verrucaria; ピラマン型ジテルペノイド

During the course of our screening program for novel antitumor antibiotics, we have recently isolated two new pimarane-type antitumor antibiotics named myrocin C and B from the culture filtrate of a soil fungus, Myrothecium verrucaria strain No. 55. The structures of myrocin C and B were characterized as a pentacyclic pimarane diterpene composed of a gamma -lactol group and a unique cyclopropane ring on the basis of its physico-chemical properties and spectroscopic data as well as a single-crystal X-ray diffraction analysis of myrocin C monoacetyl derivative, namely 1, 20-cyclo-6, 6, 9-trihydroxy-19-oic-7-oxo-8, 15-pimaradiene-19, 6-gamma -lactone and its 11-oxo derivative. In addition to a related compound named 55-0 substance was isolated from the same metabolite. Mainly, from the comparison of various spectral data between myrocin C, B and 55-0, its structure was proposed as 9-hydroxy7-oxo-1, 5, 8, 15-pimaratetraene-19, 6-gamma -lactone.From the other fungus, new active substances, a chlorine-containing shikimate-related metabolite and 3-methoxy-2, 5-toluquinine, were isolated from soil collected near Sakai City. The structure including absolute stereochemistry of the chlorine-containing metabolite was established by spectroscopic and X-ray crystallographic studies as (1R, 6R, 9S, 10S)-9-chloro-10-hydroxy-8-methoxycarbony1-4-methylene-2, 5-di-oxabicyclo[4.4.0] dec-3-one-7-ene.These antibiotics were effective against some Gram-positive bacteria, fungi and yeasts. It is particularly noteworthy that myrocin B and C had a good therapeutic effect on mice infected with Ehrlich ascites carcinoma, with the prolongation rate (T/C) of 169% at a dose of 2.4 m g/kg being significantly higher that than of myrocin C (130%). Cytotoxic effect of chlorine-containing metabolite against murine lymphocytic leukemia P-388 cells is a comparable effect to that obtained for 5-fluorouracil.

在我们筛选新型抗肿瘤抗生素的过程中，我们最近从土壤真菌疣状漆斑菌55号菌株的培养滤液中分离到两种新的匹马烷型抗肿瘤抗生素，命名为myrocin C和B。根据其物理化学性质和光谱数据以及黑曲霉素C单乙酰衍生物的单晶X-射线衍射分析，即1，20-环-6，6，9-三羟基-19-酸-7-氧代-8，15-海松二烯-19，6-γ-内酯及其11-氧代衍生物。除了从同一代谢产物中分离出一种名为55-0的相关化合物外，还分离出一种物质。通过对myrocin C、B和55-0的各种光谱数据的比较，推测其结构为9-hydroxy 7-oxo-1，5，8，15-pimaratetraene-19，6-gamma -lactone。经光谱学和X-射线晶体学研究，确定其结构为（1 R，6 R，9 S，10 S）-9-氯-10-羟基-8-甲氧羰基-4-亚甲基-2，5-二氧杂双环[4.4.0]癸-3-酮-7-烯。特别值得注意的是，myrocin B和C对感染埃利希腹水癌的小鼠有较好的治疗效果，在2.4 mg/kg剂量下，T/C延长率（169%）明显高于myrocin C（130%）。含氯代谢物对小鼠淋巴细胞白血病P-388细胞的细胞毒性作用与5-氟尿嘧啶相当。

项目成果

E. Kitamura: "(1R,6R,9S,10S)ー9ーChloroー10ーhydroxyー8ーmethoxycarbonylー4ーmethyleneー2.5ーdioxabicyclo[4.4.0]decー3ーoneー7ーene. A First Chlorineーcontaining Shikimate related Metabolite from Fungi." Tetrahedron Lett.31. 4605-4608 (1990)

E.北村：“(1R,6R,9S,10S)－9－氯－10－羟基－8－甲氧基羰基－4－亚甲基－2.5－二氧杂双环[4.4.0]dec－3－酮－7－烯。A第一个含有来自真菌的莽草酸相关代谢物的氯。”Tetrahedron Lett.31. 4605-4608 (1990)

Eiji Kitamura: "(1R, 6R, 9S, 10S)-9-Chloro-10-hydroxy-8-methoxycarbony1-4-methylene-2, 5-dioxabicyclo-[4.4.0]dec-3-one-7-ene, A First Chlorine-containing Shikimate-related Metabolite from Fungi" Tetrahedron Lett.31. 4605-4608 (1990)

Eiji Kitamura：“（1R，6R，9S，10S）-9-氯-10-羟基-8-甲氧基羰基1-4-亚甲基-2，5-二氧杂双环-[4.4.0]dec-3-one-7-ene

E.Kitamura: "(1R,6R,9S,10S)ー9ーChloroー10ーhydroxyー8ーmethoxycarbonylー4ーmethleneー2,5ーdioxabicyclo[4.4.0]decー3ーoneー7ーene.A First Chlorineーcontaining Shikimate related Metabolite from Fungi." Tetrahedron Lett.31. 4605-4608 (1990)

E.Kitamura：“(1R,6R,9S,10S)－9－氯－10－羟基－8－甲氧基羰基－4－亚甲基－2,5－二氧杂双环[4.4.0]dec－3－酮－7－烯.第一个含有来自真菌的莽草酸相关代谢物的氯。”Tetrahedron Lett.31. 4605-4608 (1990)