Zhang Meng, Yin Da-li, Liu Hong-yan, Guo Ji-yu, Liang Xiao-tian
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
Yao Xue Xue Bao. 2003 Jun;38(6):424-9.
To design and synthesize a series of new taxoids with a 5-O-sidechain, and to test the multi-drug resistant reversal activity of these compound on KB/V200 cells which is 180 times more resistant to vincristine.
Using Sinenxan A as a common synthetic starting material, three different types of 5-O-sidechain molecules were synthesized through different route. For type I compounds, 14-acetoxy of Sinenxan A was selectively removed by hydrolysis, xanthation and reduction with tributyltin; A C-10-oxo group was introduced by PCC oxidation; 5-O-acetyl group was selectively removed by potassium tert-butoxide and finally the side chain was introduced by acylating with the corresponding acid. For type II compounds, 5-O-sidechain was introduced to the 5-deacetyl Sinenxan A which was obtained by selective hydrolysis with tBuOK. For type III compounds, 9-acetoxy group was introduced, then 5-OH was left free by thorough hydrolysis and reacetylation. Acylation at 5-position, the final product was obtained. Structure of the compounds have been confirmed by FABMS and 2DNMR. The activity of the compounds in vitro was tested on KB/V200 resistant cell line using MTT method.
Nine compounds showed resistant reversal activity and enhancing the cytotoxicity of vicristine against KB/V200 cells. Compounds I2, I3, I4 restored the sensitivity of KB/V200 towards vicristine to a level of IC50 at 1 x 10(-8) mol.L-1 which is better than the positive control Verapamil.
The drug resistant reversal activity of taxane derivatives can be affected by substitution at different positions and the length of side chains of Sinenxan A. It is worthy to be further studied.
设计并合成一系列带有5-O-侧链的新型紫杉烷类化合物，并测试这些化合物对长春新碱耐药性高出180倍的KB/V200细胞的多药耐药逆转活性。
以辛夷酰氯A作为共同的合成起始原料，通过不同路线合成了三种不同类型的5-O-侧链分子。对于I型化合物，辛夷酰氯A的14-乙酰氧基通过水解、黄原酸化和用三丁基锡还原选择性地除去；通过PCC氧化引入C-10-氧代基团；用叔丁醇钾选择性地除去5-O-乙酰基，最后通过用相应的酸酰化引入侧链。对于II型化合物，将5-O-侧链引入通过用叔丁醇钾选择性水解得到的5-去乙酰基辛夷酰氯A。对于III型化合物，引入9-乙酰氧基，然后通过彻底水解和重新乙酰化使5-OH游离。在5位进行酰化，得到最终产物。化合物的结构已通过FABMS和二维核磁共振得到证实。使用MTT法在KB/V200耐药细胞系上测试化合物的体外活性。
九种化合物显示出耐药逆转活性，并增强了长春新碱对KB/V200细胞的细胞毒性。化合物I2、I3、I4将KB/V200对长春新碱的敏感性恢复到IC50为1×10⁻⁸mol·L⁻¹的水平，优于阳性对照维拉帕米。
紫杉烷衍生物的耐药逆转活性可能受辛夷酰氯A不同位置的取代和侧链长度的影响。值得进一步研究。
