| Abstract:VBE-1has been confirmed as the main bioactive component of traditional Chinese medicine Fructus Viticis Negundo, which exerted outstanding anti-tumor effect in vitro by inhibiting Akt-mTOR pathway. However, pharmacodynamic study showed that VBE-1metabolite quickly in vivo, leading to an obvious inconsistence of activity in vitro and in vivo.Compared with VBE-1, Podophyllotoxin and Etoposide have similar chemical structures and have been used as classic anti-tumor drugs. But these anti-tumor drugs have common problems, such as narrow anticancer spectrum, poor water solubility, severe myelosuppression and gastrointestinal damages.Aiming at inhibiting quick metablisation of VBE-1, we tried to modify VBE-1by substituting C-41and C-6hydroxyl groups to modify Podophyllotoxin in the light of the chemical structure of VBE-1, in order to reduce its toxicity. Therefore, the object of the research is to find a series of compounds which have ideal activity as Podophyllotoxin and high safety as VBE-1.In this object, we use Podophyllotoxin and VBE-1as starting materials.24target compounds were synthesized, which, can be divided into3series:Etoposide4’-alkylation derivatives, VBE-14’-alkylation derivatives and Podophyllotoxin derivatives. All synthesized target compounds were confirmed by spectroscopic methods. And were tested for their inhibitory effect against NCI-H446cell lines using plate clone-formation method. And19of them have anti-tumor effect.The preliminarily structure-activity relationship (SAP) of VBE and Etoposide derivatives were summarized:the length of side chain had obvious affect on the activity of compounds,2-aldehyde group and3-hydroxymethyl group were important functional groups, if is substituted by ester, activity would be reduced. Based on literatures, herein, could lay a solid foundation of finding ideal anti-tumor drugs.There are35figures,12tables and48references in this paper. |
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