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

本研究的第一个目的是通过测试大环内酯类抗生素（特别是夹竹桃霉素）的苷元（被认为是生物合成前体）与夹竹桃霉素生产生物链霉菌抗生素的阻断突变体的结合，阐明生物有机化学的大环内酯类抗生素的生物合成过程。第二是通过掺入非天然苷元制备新的大环内酯类抗生素。以夹竹桃霉素(1)为原料合成了(8ro - 8,8 a-脱氧夹竹桃内酯(2)、(8R, 9S)-9-二氢- 8,8 a-脱氧夹竹桃内酯(3)、(9R)-9-二氢- 8,8 a-脱氢- 8,8 a-脱氧夹竹桃内酯(4)、8,8 a-脱氢- 8,8 a-脱氧夹竹桃内酯(5)和夹竹桃内酯(6)。利用高效液相色谱（HPLC）和抗菌活性对制备的突变体进行鉴定，分析了这些苷元与突变体的结合情况。苷元5和6与1的结合效率最高，其他苷元的结合效率较低。这开启了逻辑生物合成途径为2->3->4->5->6->1的可能性。另一方面，其他化学合成的苷元：(8S)-8-羟基-8-碘甲基齐墩墩内酯、8-氟甲基齐墩墩内酯、9-溴齐墩内酯和9-氨基齐墩内酯则没有。转化为相应的新型抗生素。虽然开发具有较低物质特异性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最佳方法。

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.