Synthesis, Anti-Cancer And Antioxidation Activities Studies Of Stable Nitroxyl Radicals Spin-Labeled Podophyllotoxin Derivatives

Podophyllotoxin, is a naturally occurring cyclolignan compound. A number of biological activities such as cytotoxicity, antiviral, antirheumatic, insecticidal, etc., have been reported for podophyllotoxin and several related compounds and derivatives. Among them, the antitumor activity is the most attractive, making it as a lead compound for anticancer drug design and development. The stable nitroxides have a wide range of activities in biological tissues. Some studies have shown that the introduction of a nitroxyl moiety can lower general toxicity and improved the antitumor activity of the drug. Nitroxides possess superoxide dismutase (SOD) mimetic activity and have been shown to prevent oxidative damage in various biological systems.In order to obtain the effective therapeutic agents with high activities and less toxic to normal cells, two kinds of stable nitroxyl radicals spin-labeled podophyllotoxin derivatives were designed, synthesized and evaluated for their antitumor activity, antioxidant activity and lipid-water partition coefficient in this thesis.1. Based on 4β-NH2-4'-demethylepipodophyllotoxin as materials, take into account the L-amino acids with better biological activity in human body, five spin labeled derivatives of podophyllotoxin compounds were synthesized though associated 4β-NH2-4'-demethylepipodo phyllotoxin and pyrroline stable nitroxyl radicals with natural L-amino acid as linker. As the results, most target compounds showed more effective superior or comparable cytotoxicities than VP-16, against human lung carcinoma (A-549), human leukemic (HL-60) and myeloma cells (RPMI-8226) in vitro. But against leukemia cells (K562) activity more than the parent compound but less than VP-16; and less antitumor avtivity on hepatocarcinoma (HepG2) than VP-16 and parent compounds. At the same time, the lipid-water partition coefficient of the compounds to be improved; all the compounds showed significantly antioxidant activity better than the parent compound and VP-16. 2. Based on 4β-NH2-4'-demethylepipodophyllotoxin as materials, seven spin labeled podophyllotoxin derivatives compounds were synthesized though associated 4β-NH2-4'-demethylepipodophyllotoxin and piperidine stable nitroxyl radicals with natural L-amino acid as linker. We found most of target compounds showed more effective superior or comparable antitumor activity than VP-16, against human lung carcinoma (A-549), human leukemic (HL-60) and myeloma cells (RPMI-8226) in vitro. But against leukemia cells (K562) activity more than the parent compound but less than VP-16; and less antitumor avtivity on hepatocarcinoma (HepG2) than VP-16 and parent compounds. The lipid-water partition coefficient of the compounds to be improved a certain extent; all the compounds showed significantly antioxidant activity better than the parent compound and VP-16 too.