Design And Evaluation Of Ginkgolic Acid Derivatives As Antitumor Agents

Malignant cancer is one of the major diseases to threat human health.To find effective anti-cancer drugs has become a research hotspot. Because of the synthetic drugs following serious side effects in the chemotherapy,drugs from natural plants with high activity and low toxicity are attracting increasing attention and favor.Ginkgolic acid(GA),one of the active components,is being in the leaves,fruits and sarcotestas of Ginkgo biloba.It was reported that GA had inhibited the growth on cancer cells and induced apoptosis of tumor cells in vitro.GA was also been found to inhibit tumor growth and prolong survival of tumor-bearing mice in vivo.It has been considered a highly R & D potential of anti-cancer active compounds.To find out more effective anti-cancer active compounds,author studied the structure-activity relationship of ginkgolic acids.The structures of ginkgolic acids were modified that refering to the anacardic acids modification methods.The anti-cancer activities of the new derivatives of GAs were determined by MTT method.The main contents of the present work are as follows:1) As the starting material,ginkgolic acids were separated from sarcotestas of ginkgo biloba in which the content of ginkgolic acids was up to 5.46%.The synthetic methods of derivatives from ginkgolic acids were investigatied.The following synthetic methods were collected:such as nitration,decarboxylation,and oxidative cleavage.The 8-[(2-carbohydroxy-3-hydroxy)phenyl]octanal,5-nitroanacardic acids, bilobol and were synthesized,respectively.Their structures had been established by IR and UV.2)The anti-cancer activities against several cancer lines (SMMC-7721,BGC-823,A549,K562,L1210) were determined by MTT method in vitro.The results showed that bilobol appeared the strongest anti-cancer activities in all derivatives.The IC₅₀ of bilobol on SMMC cell was 3.36 mg/L,which is lower than that of ginkgolic acids(6.5 mg/L).3) The method of bilobol of monomers preparation was studied.The preparative column was ZORBAX SB-C18(250 mm×9.4 mm,5μm ). The mobile phase consisted of a mixture of methanol-3%glacial acetic acid(90:10,V:V) with a flow rate of 3.0ml/min.The detection wavelength was at 275nm.The column temperature was 40℃.Results indicate that the developed HPLC can be utilized.The purities of three main components were up to 95%.The three bilobol monomers were confirmed by UV,IR,¹HNMR,¹³C-NMR and GC-MS.4) The growth inhibition effects of bilobol C13:0,C15:1 and C17:1 on SMMC-7721 cells were tested by MTT method.Bilobol C17:1 showed the strongest inhibiting effect in three monomers.This results revealed a structure-activity relationship rule.The bilobol with unsaturated side chain had stronger inhibition effect than that with saturated side chain.In the bilobol with unsaturated side chain,the bilobol C17:1 appeared stronger inhibition effect than C15:1.It provides an important reference for studying the design and the structure-activity relationship of new GAs derivatives.