摘要：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.rn 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.
