| Objective: The natural podophyllotoxin have significant anti-tumor therapeutic effect,the marketed drugs, synthesized by podophyllotoxin such as etoposide, teniposide and etoposide phosphate has been used as first-line drugs. However, there are lots of limitations for them to be used widely in clinic such as gastrointestinal disturbances,myelosuppression, poor solubility in water and drug resistance. Therefore, our team has synthesized podophyllotoxin derivatives aiming to make the drug less toxic,anti-multidrug resistant and more effective.Content: By the early transformation of podophyllotoxin we found that coumpouds exibit a higher anti-tumor activity when its C-4 substituted by N was linked to furan ring. However, these compounds have been metabolized rapidly in vivo, which has become a problem for us to overcome. Moreover, whether the furan ring can be replaced by other cyclic structures need further research. In addition, the majority of the substituent groups we had attached are acidic and less polar. Therefore, we would like to prepare derivatives with more polar and basic substituents, and study their activities. Furthermore, we will prepare the derivatives containing fragments from several new drugs that are known to be anti-drug resistant, and test their activities.Methods: According to the structure-activity relationship studies of other literatures and those from our team, we have synthesized four series of 36 novel podophyllotoxin derivatives. Series A, the podophyllotoxin amides and Schiff base,have been synthesized by condensation reaction to link the indole and furan ring. The compounds of series B have been synthesized by amino protection, the condensation reaction to link the thiophene ring or a thiazole ring. Series C, podophyllotoxin urea with aniline, benzylamine and related substituents, was synthesized by the same method. Series D, podophyllotoxin derivatives linked with piperazine cyclic or other secondary amines, was synthesized by anhydride reaction. These compounds were evaluated for the antitumor activities in vitro by MTT method with the etoposide as positive control, which has been used in the treatment small cell lung cancer as first-line medicine.Result: Finally, we have designed and synthesized 36 podophyllotoxin derivatives and they have been characterized with 1H-NMR ?13C-NMR?HR-ESI-MS. These coupounds have not been reported. The screening results indicate that compound A-4,A-7, B-2, C-1, C-2, C-4, D-4 are more effective and need for further antitumor test in vivo. Compound B-7, B-9, C-7 have considerable activity of inhibiting tumor cell proliferation in vitro and need toxicity testing on normal cells. Compound A-7 has good water solubility, high activity and resistance to K562/A02, which need further study.Conclusion: The synthesized compounds A-4, A-7, B-2, C-1, C-2, C-4,D-4 have good anti-tumor activity, which indicates the connected structural fragment such as furan methylamine, fluoro-substituted benzylamine and thiophene carboxylic acid do improve the activity and have good water solubility. But it still requires animal tests to give more evidence. Compound A-3, A-7, C-3 has good activity against K562/A02,which requies the mechanism studies. Based on the structure-activity relationships,this paper has summarized systematicly and proposed some recommendations for seeking new compounds with higher efficiency, specific-targeting and anti-multidrug resistance, which lay the foundation for further study of podophyllotoxin antitumor drugs. |
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