Total synthesis of the antitumor depsipeptide FR-901,228
Total synthesis of the antitumor depsipeptide FR-901,228
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DOI：
10.1021/ja9613724
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发表时间：
1996-07-31
影响因子：
15
通讯作者：
Simon, JA
中科院分区：
文献类型：
--
作者：
Li, KW;Wu, J;Simon, JA
1982年Ha-ras基因突变的发现首次表明了调节蛋白的特定分子变化与癌症之间的联系。1-3突变ras蛋白，其中缬氨酸取代甘氨酸-12，被证明能够诱导小鼠成纤维细胞（NIH-3 T3）的形态变化。在这些细胞中，转化的表型指示致癌活化并与致瘤性增加相关。最近，已经鉴定了多种天然产物和合成药物，其逆转这种表型并因此“去转化”致瘤细胞系。其中包括根酚4、5和酪氨酸磷酸酶抑制剂6、来普霉素B、7、8、L-739、749、9和trapoxin A。10，11使用Ha-ras转化的NIH-3 T3细胞的表型逆转试验，从陆生细菌紫色色杆菌的培养液中分离出这一类别的新成员FR-901，228（1）。FR-901，228在动物试验中也显示出高活性。12-14这一发现并不令人惊讶，因为药物逆转致癌转化的形态学效应的能力通常伴随着体内抗肿瘤活性。FR-901，228活性的分子基础尚未确定。15 FR-901，228（1）（图1）是一种双环缩酚肽，在结构上与已知类别的环肽无关。[16]除了一种α-氨基酸Z-丁酸外，缩肽还含有一种不寻常的结构单元，（3S，4 E）-3-羟基-7-巯基-4-庚烯酸5a。该硫醇与
The identification in 1982 of a mutation in the Ha-ras gene provided the first indication of a link between specific molecular changes in regulatory proteins and cancer. 1-3 The mutant ras protein, in which valine replaces glycine-12, was shown capable of inducing morphological changes in mouse fibroblast (NIH-3T3) cells. In these cells the transformed phenotype is indicative of oncogenic activation and correlates with increased tumorigenicity. Recently, a diverse class of natural products and synthetic drugs has been identified that reverses this phenotype and hence “de-transforms” tumorigenic cell lines. Among these are radicicol4, 5 and the tyrphostins, 6 leptomycin B, 7, 8 L-739,749, 9 and trapoxin A. 10, 11 A new member of this class, FR-901,228 (1), was isolated from the culture broth of the terrestrial bacterium Chromobacterium Violaceum using a phenotypic reversion assay of Ha-ras transformed NIH-3T3 cells. FR-901,228 was also shown to be highly active in animal-based assays. 12-14 This finding is not surprising since the ability of a drug to reverse the morphological effect of oncogenic transformation is often accompanied by in vivo antitumor activity. The molecular basis for either activity of FR-901,228 has yet to be identified. 15FR-901,228 (1)(Figure 1) is a bicyclic depsipeptide structurally unrelated to known classes of cyclic peptides. 16 In addition to a dehydro amino acid, Z-butyrine, the depsipeptide incorporates an unusual building block,(3S, 4E)-3-hydroxy-7-mercapto-4-heptenoic acid 5a. A disulfide bond between this thiol and