Dissertation > Medicine, health > Chinese Medicine > Of Pharmacy > Traditional Chinese medicine chemical

Design, Synthesis and Biological Evaluation of Novel Podophyllotoxin Derivatives as Antitumor Agents

Author WangLi
Tutor HuYongZhou
School Zhejiang University
Course Pharmacy
Keywords podophyllotoxin etoposide cytotoxicity antitumor activity anti-drug-resistance structure-activity relationship
CLC R284
Type Master's thesis
Year 2011
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Podophyllotoxin (PDT), a kind of aryltetralin lignans, shows multiple biological effects such as anti-fungal, anti-tumor, anti-virus, anti-insect activities. Etoposide (VP-16) and teniposide (VM-26) are two semi-synthetic derivatives of podophyllotoxin, which have been officially approved for clinical use against various types of cancers including breast cancer, testicular cancer, non small-cell lung cancer, lymphoma and childhood leukemia. However, VP-16 and VM-26 exhibit several toxic side effects, acquired drug-resistance and poor water-solubility, which block their further application. Therefore, it remains a hotspot for medicinal chemists to develop novel anticancer agents with high efficacy and-low toxicity.In previous studies, we reported a series of C-4β-N-substituted podophyllotoxin derivatives. Further biological evaluation showed that C-4β-anilino derivatives were effective in the treatment of cancer in drug-sensitive and drug-resistant xenograft models. Based on the structural features of the above-mentioned compounds, rational drug design principle were utilized and 44 novel 4β-susbtitued anilino-4’-O-demethyl-4-desoxypodophyllotoxin (series E, GL and O) were designed, synthesized, and confirmed by IR,1H NMR, 13C NMR and MS. In vitro cytotoxicities were tested against four human tumor cell lines, and most compounds showed improved activities against 95D and KB/VCR when compared to VP-16. The inhibitory rate of GL-3 on Sarcoma S180 in mice was 58.1%, which is higher than that of positive control cisplatin (45.8%). GL-3 could significantly inhibit the tumor growth (57.3%) on highly metastatic human lung cancer xenograft in nude mice. It is worthy to make further research about this compound to be a novel anticancer agent.Based on the extremely significant role that the disulfide bond played in the natural antitumor agents, we introduced this important moiety as a substituent to 4 position of podophyllotoxin.8 novel 4’-O-demethyl-4-desoxypodophyllotoxin derivatives containing disulfide side chain were designed, synthesized, and confirmed by 1H NMR and MS. Most compounds exhibited moderate or more potent cytotoxic activities than that of VP-16, especially the cytotoxicities against human leukemia cell line K562 with 2.5-38 folds more potent than that of VP-16. Besides, most of the compounds showed better anti-drug-resistant activities than that of VP-16.

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