Antitumor and antioxidant activity of spin labeled derivatives of podophyllotoxin (GP-1) and congeners.
The spin labeled derivative of podophyllotoxin, i.e. podophyllic acid-[4-(2,2,6,6,-tetramethyl-1-piperidyloxy)] hydrazone (GP-1,2) and its congeners (GP-1-OH,3, GP-1-H, 4) were synthesized. The inhibition activity to the transplanted tumor S180 and HepA and the LD50 values of these compounds in mice were tested. Their partition coefficients and pKa values were measured. The results showed that the anticancer activity of these compounds followed the order GP-1 >GP-1-OH> GP-1-H. It can be attributed to the influence of their partition coefficients and ionization constants to the compounds properties. Meanwhile, the antilipoperoxidative activities of GP-1, GP-1-OH and GP-1-H to MDA formation of liver homogenate of rat induced by Fe2+-ascorbic acid were measured. Electrochemical studies were carried out to measure the redox midpoint potentials. The relationship between the redox midpoint potentials and the antilipoperoxidative activity followed the same order as the antitumor activity. The EPR (Electron Paramagnetic Resonance) spectroscopy of the blood from carotid artery of anesthetized Wistar rat in vivo was measured. The results indicated that there is an equilibration between GP-1 and GP-1-OH, furthermore, GP-1-H can be oxidized partly to GP-1 and equilibrated with GP-1-OH in vivo. The EPR signal intensity of GP-1 is stronger than GP-1-OH and GP-1-H. It can be concluded that the oxidative state of nitroxide in compounds play a key role to the antioxidant activity.
Tian
Xuan
X
National Laboratory of Applied Organic Chemistry, Lanzhou University, PR China. xuant@lzu.edu.cn
Zhang
Fu-Min
FM
Li
Wen-Guang
WG
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D007928:Lethal Dose 50; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D011199:Potentiometry; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013113:Spin Labels; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D013113:Spin Labels; D011034:Podophyllotoxin