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Synthesis and Biological Evaluation of Antifungal Antibiotics, Spirofungin A and B

抗真菌抗生素螺芬净 A 和 B 的合成及生物学评价

基本信息

批准号：
16590026
负责人：
SHIMIZU Takeshi
金额：
$ 2.3万
依托单位：
RIKEN
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Reveromycin A (1) is a novel polyketide-type antibiotic with strong biological activity that makes it potentially useful for treatment of tumor, hyperpotassemia and bone disease. Spirofungins A (2) and B (3) are also polyketide-type antibiotics isolated from Streptomyces violaceusniger Tu 4113 as a mixture of 2:3 in the ratio of 4:1 and show various antifungal activities, particularly against yeasts. The molecular structures of 1,2 and 3 are characterized by a 6,6-spiroketal core bearing two unsaturated side chains ending in carboxylic acid units and two alkyl groups. We have already reported the first asymmetric total synthesis of 1. In connection of our studies concerning the chemical modifications and structure-activity relationships of 1, we examined the synthesis 2 and 3. The relative configuration of the spiroketal core in 2 is quite similar to that of 1. The absolute configuration depicted for 2 was proposed by analogy with 1 and remains unconfirmed. Synthetic studies of 2 were performed to confirm the absolute configuration. The 6,6-spirokeacal segment of 2 was efficiently prepared via the coupling reaction of the Weinreb amide 4 and the alkyne 5 which are readily available from the common intermediate 8. The right side chain of 2 was also constructed using vinyl borane 9 derived from 8. Finally, asymmetric total synthesis of spirofungins A (2) and B (3) has been accomplished with a longest linear sequence of 31 steps, affording (-)-2 and (+)-3 in 7.9% and 5.2% overall yields, respectively. Effects of (-)-2 and (+)-3 on both isoleucyl-tRNA synthetase activity and morphological reversion of src^<te>-NRK cells were examined. Spirofungin A (-)-2 showed weak activities for both assays.

回复霉素A（1）是一种新型的聚酮类抗生素，具有很强的生物活性，在治疗肿瘤、高钾血症和骨病等方面具有潜在的应用价值。螺旋霉素A（2）和B（3）也是从紫色黑链霉菌Tu 4113中分离的聚酮型抗生素，以2：3的比例以4：1的比例混合，并显示出各种抗真菌活性，特别是抗酵母。化合物1、2和3的分子结构特征为6，6-螺缩酮核，带有两个末端为羧酸单元的不饱和侧链和两个烷基。我们已经报道了1的首次不对称全合成。结合我们对1的化学修饰和构效关系的研究，我们研究了合成2和3。2中螺缩酮核心的相对构型与1非常相似。2的绝对构型是通过与1类比而提出的，但仍未得到证实。进行2的合成研究以确认绝对构型。2的6，6-螺酮醛片段通过Weinreb酰胺4和炔5的偶联反应有效地制备，所述Weinreb酰胺4和炔5容易地从共同中间体8获得。2的右侧链也使用衍生自8的乙烯基硼烷9构建。最后，螺旋霉素A（2）和B（3）的不对称全合成已完成，最长的线性序列为31步，分别以7.9%和5.2%的总收率得到（-）-2和（+）-3。研究了（-）-2和（+）-3对src^ -NRK细胞异亮氨酰-tRNA合成酶活性和形态逆转的影响<te>。螺芬净A（-）-2对两种试验均显示弱活性。