Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
Eur J Med Chem. 2012 Jun;52:242-50. doi: 10.1016/j.ejmech.2012.03.024. Epub 2012 Mar 23.
Starting from commercial available natural product oridonin (1), a practical synthesis of ent-6,7-seco-oridonin derivatives (2, 3, 5, and 9) was accomplished and their biological activities were evaluated. The conversion of spirolactone-type diterpenoid to enmein-type was first completed. The results demonstrated that all synthesized ent-6,7-seco-oridonin derivatives could markedly inhibit the proliferation of cancer cells. Compared with Taxol, the most cytotoxic compound 5 has similar potency in A549 cell and slightly less cytotoxicity in Bel-7402 cell. Compound 5 was also more potent than parent compound oridonin in mice with MGC-803 gastric cancer in vivo. Then a series of novel 14-O-derivatives of 5 were further designed and synthesized, which showed better activity than 5 and similar activity as Taxol in vitro. The structure-activity relationships of oridonin derivatives were also discussed in the present investigations.
从商业可得的天然产物冬凌草甲素（1）出发，完成了具有实用价值的-ent-6,7-断环冬凌草甲素衍生物（2、3、5 和 9）的合成，并对其生物活性进行了评估。首次完成了螺内酯型二萜转化为恩美宁型的转化。结果表明，所有合成的-ent-6,7-断环冬凌草甲素衍生物均可显著抑制癌细胞的增殖。与紫杉醇相比，最具细胞毒性的化合物 5 在 A549 细胞中具有相似的效力，在 Bel-7402 细胞中略低。化合物 5 在体内具有 MGC-803 胃癌的小鼠中也比母体化合物冬凌草甲素更有效。然后进一步设计和合成了一系列新型的 5 的 14-O-衍生物，其在体外显示出比 5 更好的活性，与紫杉醇的活性相似。在本研究中还讨论了冬凌草甲素衍生物的构效关系。
