A concise total synthesis of the notoamides C and D
A concise total synthesis of the notoamides C and D
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DOI：
10.1002/anie.200604377
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Williams, Robert M.
中科院分区：
文献类型：
--
作者：
Grubbs, Alan W.;Artman, Gerald D., III;Williams, Robert M.
在过去的几年里，从真菌中分离出的具有有趣生物活性的新代谢物激增。我们的研究小组在色氨酸、异戊二烯、脯氨酸和脯氨酸衍生物衍生的真菌代谢物的合成[1]和生物合成[2]的阐明方面有着丰富的历史。[3]最近，两个研究小组报告了从海洋环境中培养的两种不同真菌菌株中分离出的结构相关的生物碱。Tsukamoto及其同事最近从从普通贻贝（Mytilus edulis）培养的曲霉属海洋菌株中分离出四种新的异戊二烯化吲哚生物碱，命名为notoamides A-D（1-4，方案1），沿着已知的生物碱sclerotiamide和千金藤菌素A（9）。[4]notoamides A-D的结构含有类似于在stephacidins [5，6]和几种paraherquamides中发现的吡喃吲哚环系统。[7]此外，notoamide A（1）和B（2）具有桥连的[2.2. 2]二氮杂辛烷环系统常见于对海夸胺和千金藤素家族。有趣的是，notoamide A的2-羟吲哚部分的氮原子被氧化成N-羟基。N-甲酰胺C（3）和D（4）缺少1和2的桥连双环，4含有吡咯并吲哚环系统。[8]2005年，Hans-Knöll研究所的研究人员报道了一个相关的生物碱家族，norgeamides（5-8，方案1）。[9]这些化合物是从生长在北海的一种冷水真菌中分离出来的[9]，与3和4有着惊人的相似之处。然而，降冰片酰胺的区别特征是脯氨酸环的α位（在C17处）对于降冰片酰胺A（5）具有甲氧基取代基，并且对于降冰片酰胺B（6）和D（8）具有羟基。关于降冰片酰胺的生物活性，已经发现所有降冰片酰胺都以不同的功效抑制多种癌细胞系的生长。据报告，降冰片酰胺A（5）是最有效的细胞生长抑制剂，观察到的抑制值为77-98%。降冰片酰胺B（6）与5的区别仅在于C17位的取代，其抑制细胞生长的有效性低20-30%。降冰片酰胺C（7）和D（8）是该生物碱家族的最差抑制剂，仅观察到34-41%的抑制。与notoamides相比，它是合理的假设，脯氨酸环系统的氧化态是至关重要的生物活性。
The past several years have seen an explosion of new metabolites that are isolated from fungi and have interesting biological activities. Our research group has a rich history in the synthesis [1] and elucidation of the biosynthesis [2] of fungal metabolites derived from tryptophan, isoprene, proline, and proline derivatives.[3] Recently, two research groups have reported structurally related alkaloids that were isolated from two different strains of fungi, cultivated from marine environments. Tsukamoto and co-workers recently isolated four new prenylated indole alkaloids named the notoamides A–D (1–4, Scheme 1), along with the known alkaloids sclerotiamide and stephacidin A (9), from a marine strain of Aspergillus sp. cultivated from the common mussel, Mytilus edulis.[4] The structures of the notoamides A–D contain a pyranoindole ring system similar to those found in the stephacidins [5, 6] and several paraherquamides.[7] In addition, notoamide A (1) and B (2) possess the bridged [2.2. 2] diazaoctane ring system commonly found in the paraherquamide and stephacidin family. Interestingly, the nitrogen atom of the 2-oxindole moiety of notoamide A is oxidized to the N-hydroxy group. The notoamides C (3) and D (4) lack the bridged bicycle of 1 and 2, and 4 contains the pyrrroloindole ring system.[8] The notoamidesA–C exhibit moderate cytotoxicity against a panel of cancer cell lines but notoamide D shows no such activity.In 2005, a related alkaloid family, the norgeamides (5–8, Scheme 1), was reported by researchers at the Hans–Knöll Institute.[9] These compounds were isolated from a strain of cold water Aspergillius fungi growing in the North Sea [9] and bear a striking resemblance to 3 and 4. However, the distinguishing feature of the norgeamides is that the α position of the proline ring (at C17) has a methoxy substituent for norgeamide A (5) and a hydroxy group for norgeamide B (6) and D (8). As for the biological activity of the norgeamides, all have been found to inhibit the growth of a variety of cancer cell lines with different efficacies. Norgeamide A (5) was reported to be the most potent inhibitor of cell growth with observed values of 77–98% inhibition. Norgeamide B (6), which only differs from 5 in the substitution at the C17 position, was 20–30% less effective at inhibiting cell growth. The norgeamides C (7) and D (8) were the poorest inhibitors of this family of alkaloids with only 34–41% inhibition being observed. In comparison with the notoamides, it is reasonable to assume that the oxidation state of the proline ring system is vital for biological activity.