Synthesis and Antitumor Activity of Novel Spin Labeled Podophyllotozin Derivatives
Three novel nitroxyl labeled derivatives of podophyllotoxin 5-7 have been synthesized andevaluated for their antitumor activity against mouse leukemia L1210 cell in vitro. Compounds 5exhibited superior activity to clinically used etoposide (VP-16, 2) in its inhibition of this cell line. Podophyllotoxin (1, Figure 1) derivatives have received significant attention in recent years as aresult of the development of etoposide (VP-16, 2) and teniposide (VM-26, 3) as anticancer drugs.Etoposide shows good clinical effects against several types of tumors, including testicular and smallcell lung cancers, lymphoma, leukemia, and Kaposi”s sarcoma.1 It is believed that such analogues of4”-demethylpodophyllotoxin exert their antitumor activity through stabilization of a cleavablecomplex between DNA and type Ⅱ DNA topoisomerase.2,3 However, several limitations such as poorwater solubility, development of drug resistance, and metabolic in activation still exist.4 In order toovercome the limitations of 2 and develop compounds with better antitumor activity, we had designedand synthesized many novel 2 analogues. We found that a number of nitroxyl spin labeled derivativesof podophyllotoxin such as (GP-7, 4) had significant antitumor activity with marked decrease intoxicity compared to the parent compounds 1 and 2.5a Some spin labeled derivatives were alsoreported to have superiorp harmacological properties to their parent compounds.5 On the other hand,replacement of the C-4 sugar moiety of 2 with a nonsugar substitution has proven to be significant inovercoming the drug resistance of 2.6 It is also known that only compounds with β-substitution atthe C-4 position are active. In view of the available information on structure-activity relationships, wereport here the synthesis of the three novel 4β-nitroxyl labeled analogues of 4”-demethylepipodophyUotoxin 5-7 and their antitumor activity against mouse leukemia L1210 cell invitro.
抗肿瘤活性 自旋标记 鬼臼毒素 衍生物 白血病 动物模型
Shaoyuan Chen Yongping Yu Yaozu Chen
College of Life science,Zhejiang University,Hangzhou 310027,P.R.China Department of Chemistry,Zhejiang University,Hangzhou 310027,E R.China
国内会议
杭州
英文
12-15
2004-10-01（万方平台首次上网日期，不代表论文的发表时间）