Ma Dawei, Zou Bin, Cai Guorong, Hu Xiaoyi, Liu Jun O
State Key Laboratory of Bioorganic and Natural Products Chemistry Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences 354 Fenglin Lu, Shanghai 200032, China.
Chemistry. 2006 Oct 10;12(29):7615-26. doi: 10.1002/chem.200600599.
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.
本文描述了一种新的海兔毒素A的全合成方法，关键步骤包括通过D-脯氨酸催化的直接羟醛反应和奥波泽尔反式羟醛反应构建其聚酮片段，以及通过仿生合成制备其噻唑啉单元。还通过类似方法制备了海兔毒素A的恶唑啉类似物。该化合物对HeLa细胞增殖的抑制活性仅略低于海兔毒素A，而海兔毒素A的C(40)-去甲基化恶唑啉类似物的细胞毒性则低得多，并且该新类似物的C(37)-差向异构体和C(37)去甲基化产物无活性。这些结果表明，C(37)和C(40)位的两个甲基以及C(37)位的立体化学结构对海兔毒素A恶唑啉类似物的强效细胞活性至关重要。进一步的生物学分析表明，合成的海兔毒素A及其恶唑啉类似物均通过使细胞周期停滞在G1期来抑制细胞增殖。
