Bio-Organic Studies on the Biosynthetic Pathway of Macrolide Antibiotics and the Application to the Synthesis of Useful Analogs

大环内酯类抗生素生物合成途径的生物有机研究及其在有用类似物合成中的应用

• 批准号: 02453088
• 负责人: TATSUTA Kuniaki
• 金额: $ 3.46万
• 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 (B)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-02453088/
• 关键词: Macrolide antibiotic; Oleandomycin; Aglycone; Biosynthesis; Mutant; Antibiotic; Incorporation; 生理活性物質; 生物有機化学的研究

It was the first aim of this study to clarify bio-organic-chemically the biosynthetic process of macrolide antibiotics (especially, oleandomycin) by testing the incorporation of their aglycones, which were presumed to be biosynthetic precursor, to blocked mutants of an oleandomycin-producing organism, Streptomyces antibiotics. The second was the preparation of new macrolide antibiotics by the incorporation of unnatural aglycones.The proposed aglycone-presusors, (8RO-8, 8a-deoxyoleandolide(2), (8R, 9S)-9-dihydro-8, 8a-deoxyoleandolide(3), (9R)-9-dihydro-8, 8a-dehydro-8, 8a-deoxyoleandolide(4), 8, 8a-dehydro-8, 8a-deoxyoleandolide(5)and oleandolide(6)were synthesized from oleandomycin(1). The incorporation of tmese aglycones to mutants, which were prepared by us, was assayed by identification of produced antibiotics with 1 using HPLC and antibiotic activities. The aglycones 5 and 6 were most efficiently incorporated to produce 1, but the others were done to a lesser extent. This opens the possibility that a logical biosynthetic pathway would be 2->3->4->5->6->1.On the other hand, other chemically synthesized aglycones : (8S)-8-hydroxy-8-iodomethyloleandolide, 8-fluoromethyloleandolide, 9-bromooleandolide and 9-aminooleandolide were not. converted into the corresponding new antibiotics.Although the development of mutants having lower substance-specificity is the coming problem, the present bioorganic approach is obviously the excellent method to clarify the biosynthesis of antibiotics.

这项研究的第一个目的是通过测试大环内酯类抗生素(特别是油兰霉素)的苷元(被认为是生物合成前体)与油兰霉素产生菌链霉菌抗生素的受阻突变株的掺入，从生物有机化学的角度阐明大环内酯类抗生素(尤其是油兰霉素)的生物合成过程。以齐墩果素(1)为原料合成了(8RO-8，8a-脱氧齐墩果糖(2)，(8R，9S)-9-二氢-8，8a-脱氧齐墩果糖内酯(3)，(9R)-9-二氢-8，8a-脱氧齐墩果糖内酯(3)，(9R)-9-二氢-8，8a-脱水-8，8a-脱氧齐墩果糖内酯(4)，8，8a-脱氧齐墩果糖内酯(5)和齐墩果糖(6))。通过高效液相色谱鉴定1产生的抗生素和抗生素活性，对我们制备的突变株掺入糖苷元的情况进行了检测。苷元5和6被最有效地结合生成1，而其他的结合程度较小。另一方面，其他化学合成的苷元：(8S)-8-羟基-8-碘甲基内酯、8-氟甲基内酯、9-溴内酯和9-氨基内酯则不是。尽管开发物质专一性较低的突变体是未来的问题，但目前的生物有机方法显然是阐明抗生素生物合成的优秀方法。

项目成果

Kuniaki TATSUTA: "Biosynthetic Studies on Oleandomycin by Incorporation of the Chemically Synthesized Aglycones." Journal of Antibiotics. 43. 909-911 (1990)

Kuniaki TATSUTA：“通过掺入化学合成的苷元对夹竹桃霉素进行生物合成研究。”

Kuniaki TATSUTA, Hiroki GUNJI, Shuichi TAJIMA, and Takashi ISHIYAMA: " "Biosynthetic Studies on Oleandomycin by incorporation of the Chemically Synthesized Aglycones"" Journal of Antibiotics. 43. 909-911 (1990)

Kuniaki TATSUTA、Hiroki GUNJI、Shuichi TAJIMA 和 Takashi ISHIYAMA：““通过掺入化学合成苷元对夹竹桃霉素进行生物合成研究””《抗生素杂志》。

Kuniaki TATSUTA: "Recent Progress in the Chemical Synthesis of Antibiotics." Gabor LUKACS and Masaji OHNO, 803 (1990)

Kuniaki TATSUTA：“抗生素化学合成的最新进展。”

Kazunobu Toshima: "The use of 2,6ーanhydroー2ーthio glycopyranosyl fluoride for a highly αーstereoselective glycosglation." Tetrahedron Lett.31. 6361-6362 (1990)

Kazunobu Toshima：“使用 2,6-脱水-2-硫代吡喃糖基氟化物进行高度 α-立体选择性糖基化。”31 (1990)。

Kazunobu Toshima: "The use of 2,6ーanhydroー2ーthio sugar for a highly stereocontrolled glycosylation:A novel strategy for synthesis of 2,6ーdideoxyーαーglycosides." Tetrahedron Lett.31. 3339-3342 (1990)

Kazunobu Toshima：“使用 2,6-脱水-2-硫代糖进行高度立体控制的糖基化：合成 2,6-二脱氧-α-糖苷的新策略。31。” ）