Synthesis、Anti-Cancer and Antioxidation Studies of Spin Labeled Podophyllotoxin and Chalcones Derivatives
|Keywords||podophyllotoxin chalcone stable free radicals spin labeled anticancer activity cytotoxicity antioxidation activity octanol-water partition coefficients antibacterial activity NO inhibition|
The spin labeled stable nitroxides have a wide range of activities in biology. Some study have shown that the introduction of nitroxyl moiety can leads to higher alkylating, lower carbamoylating activity, lower general toxicity, through cell membranes and protect macromolecule from oxidative damage, which offer a good means for studying the antitumor drug and their mechanism. To seek ask for the relationship of stable free radicals between the antitumor activity and antioxidative activity, and search the anticancer agent with high activities and less toxicity, a series of spin labeled podophyllotoxin derivatives and chalcones were be studied in this thesis.First, podophyllotoxin as well as its congeners exhibit pronounces biological activity especially anticancer activity. Many structures activity relationship showed that 4-site is an important factor to keep its antitumor activity, therefore, two kinds of spin labeled podophyllotoxin were designed, synthesized and evaluated for their biological activites.1. Eleven 4-βorα-substituted-piperidine （pyrroline） spin labeled podophyllotoxin and congeners were synthesized. Their cytotoxicities against human cancer cells lines （human leukemia P-388, lung cancer A549） and antioxidative activity of malondialdehyde （MDA） showed stronger inhibition than that of VP-16, also, 4β-substituted podophyllotoxin were more effective superior activity that of 4-α’s. Further, the cytotoxicity of these compounds was correlated with antioxidative activity. Aside, their partition coefficients lgP were also indicated spin labeled compounds can penetrate cell membranes easier than that of VP-16.2. To further investigate this relationship, a spin labeled derivative of podophyllotoxin GP-7 and its congeners （GP-7-H,GP-7-OH） have been prepared. The inhibition rate to the mice transplanted tumor S180 and HepA in vivo, cytotoxicity （P-388, A-549） and the malondialdehyde （MDA） on tissue of Wistar rats in vitro were tested. The results revealed their antitumor activities were consistent with that of antioxidant activities, namely, spin labeled compound was higher than congeners in activities, namely, GP-7 > GP-7-OH、GP-7-H. whereas the toxicity LD50 showed opposite results. In a word, the compound with a higher antioxidation has a higher antitumor activity and less toxicity and spin-labeled antitumor compounds have a higher cytotoxicity and lower toxicity than that of non-labeled’s.Second, to explore the above relationship of how the stable free radicals affect nature cmpounds chalcone with antioxidative capability, another series spin labeled and non-labeled chalcones were synthesized. In addition, their biological activities were determined including cytotoxity（P388、A549、HT-29、MDA-MB-231、SGC-7901、BEL-7402、MCF-7）、NO inhibition and antibacterial activity. At the same time, the results were discussed in the fifth chapter.