Total synthesis of the cyclodepsipeptide apratoxin A and its analogues and assessment of their biological activities
Total synthesis of the cyclodepsipeptide apratoxin A and its analogues and assessment of their biological activities
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DOI：
10.1002/chem.200600599
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发表时间：
2006-10-10
影响因子：
4.3
通讯作者：
Liu, Jun O.
中科院分区：
文献类型：
--
作者：
Ma, Dawei;Zou, Bin;Liu, Jun O.
采用D-脯氨酸催化的直接羟醛缩合反应和Oppolzer的反羟醛缩合反应组装其酮片段，并仿生合成其噻唑啉单元。阿曲毒素A的恶唑啉类似物也通过类似的方法进行了详细的研究。该化合物对HeLa细胞增殖的效力仅略低于黄曲霉毒素A，而黄曲霉毒素A的C（40）-去甲基恶唑啉类似物显示出低得多的细胞毒性，并且该新类似物的C（37）差向异构体和C（37）-去甲基化产物是无活性的。这些结果表明，C（37）和C（40）上的两个甲基以及C（37）上的立体化学是阿曲毒素A恶唑啉类似物有效细胞活性所必需的。进一步的生物学分析表明，合成的阿曲毒素A及其恶唑啉类似物通过引起细胞周期停滞在G1期来抑制细胞增殖。
A novel total synthesis of apratoxin A is described, with key steps including the assembly of its ketide segment through a D-proline-catalyzed direct aldol reaction and Oppolzer's anti aldol reaction and the preparation of its thiazoline unit in a biomimetic synthesis. An oxazoline analogue of apratoxin A has also been elaborated by a similar approach. This compound has a potency against HeLa cell proliferation only slightly lower than that of apratoxin A, whilst a C(40)-demethylated oxazoline analogue of apratoxin A displays a much lower cytotoxicity and the C(37)epimer and C(37)-demethylation product of this new analogue are inactive. These results suggest that the two methyl groups at C(37) and C(40) and the stereochemistry at C(37) are essential for the potent cellular activity of the oxazoline analogue of apratoxin A. Further biological analysis revealed that both synthetic apratoxin A and its oxazoline analogue inhibited cell proliferation by causing cell cycle arrest in the G1 phase.