Synthesis And Studies On Biological Activity Of New Spin-labeled Derivatives Of Podophyllotoxin

Podophyllotoxin as well as its derivatives exhibit a pronounced biological activity mainly as antitumor agents, which is a good source of the aryltetralin lignan. The etopside(VP-16),toniposide(VM-26) and etopophos are already utilized as Broad-spectrum antitumor drugs in clinical, which are derivatived from podophyllotoxin as parent compound. However, their therapeutic use is often hindered by problems such us poor water solubility,acquired drug-resistance and strong toxicity. To search for the anticancer agents with high activity and low toxicity, and study the different activity of the podophyllotoxin isomers, a series of spin-labelled compound were synthesized as well as biological activity was tested in this thesis.1. Based on the excellent anticancer activity of 4'-demethyl-4-deoxypodophyllotoxin (DDPT), as well as amino acids with a special physiological activity in vivo, eight compounds were synthesized through associated DDPT and nitroxyl radical with L-amino acid as linker.The cytotoxicity on five different cell lines and the malondialdehyde (MDA) on tissue of SD rats in vitro were tested. The results revealed all of these compounds exhibited a stronger cytotoxicity than VP-16, in particular, the IC50 values of the compound with glycine-linked reached a level of nM against HL-60, K562 and HepG2 cells. The introduction of nitroxyl moiety extremely enhanced the antioxidant activity of the compound. Compound with a linker of isoleucine displayed a more potent antioxidant activity against the kidney and liver tissues of SD rats, especially for the former with an IC50 value of 6.89μM.2.Picropodophyllin, possess a cis-lactone ring which can be transformed from podophyllotoxin, has little or no toxicity. Four pair of spin-labelled derivatives of podophyllotoxin and its isomer were synthesized, and then studied by Circular Dichroism Spectra (CD) and Thin Layer Chromatography (TLC). The derivatives of podophyllotoxin exhibited a better biological activity than its isomers'both in the cytotoxin and antioxidant test.3. The biological activity of a derivative with an opened-lactone ring is decreased comparing with podophyllotoxin, but the compound GP-11 has a lower toxicity and a comparable activity with the VP-16. To further study the physiological activity of these kinds of compounds, we design to synthesize some spin-labeled derivatives of podophyllotoxin and deoxypodophyllotoxin.This part of work is still ongoing.