Synthesis Of Caffeic Acid β-phenethyl Ester Analogues And Study On Their Anti-tumor Activity

Caffeic acid β-phenethyl ester, as one of the major biological active ingredients in propolis, has the effects of antioxidant, anti-tumor, anti-bacterial, anti-inflammatory, immunomodulatory and so on. Cancer is one of the leading cause of death, for which a common treatment is chemotherapy. When chemotherapy is used to kill cancer cells, it has many side effects such as killing healthy cells and leukopenia as well. Therefore, it is necessary to continue to seek safer and more effective anticancer drugs. In order to enhance the pharmacological activity of the PEC, its derivatives were synthesized and their anti-cancer effects, protective effects on chemotherapy were studied in this subject. This plays an important roll for its application and development.PEC and four PEC derivatives were synthesized starting from caffeic acid, ferulic acid and β-phenethyl alcohol analogues by acyl halide reaction, and characterized by MS, NMR. Their effects on cell cytotoxicity, macrophage tumor inhibition activity, nitric oxide and TNF-α production inhibition activity of macrophage in vitro was investigated by MTT or ELISA assay. The results showed that the anti-cancer effect of PEC derivatives(especially nitro substituted derivatives:PEC-3and PEC-5)on A549, HepG2was increased significantly, their IC50values were significantly reduced. They had low cytotoxicity to macrophage with more than80%macrophages survival in6.25μM-50μM. They can also promote tumor inhibition activity of macrophage in12.5μM-50μM. PEC and its derivatives could significantly reduce lipopolysaccharide-induced high levels of nitric oxide and TNF-α in12.5μM-50μM by the dose-dependent relationship. More than90%NO and60%TNF-α production can be inhibited in50uM.The protective effect of PEC and its derivatives on the leucopenia mice induce by cyclophosphamide was studied. The results indicated that most of PEC derivatives could significantly increase the reduction of mouse WBC count, spleen index, and bone marrow nucleated cell count induced by CTX, and those effects may be related to the elevated serum G-CSF, increased with the decrease of ClogP. All results indicated that PEC and its derivatives had protection effect on chemotherapy induced leukopenia. PEC derivatives, not only had a direct tumor cell killing effect, but also had indirectly anti-cancer effects by regulating macrophage tumor suppression function, inhibiting production of inflammation-related mediim NO、TNF-α.The Structure-Activity Relationships(SAR) of the compounds analysised by software, indicated that anticancer activity of PEC and its derivatives increased with the decrease of△E, with the increase of molecular dipole moment. The anti-cancer activity of PEC derivatives had been enhanced along with the change of the△E, molecular dipole moment by introduction of hydroxy, nitro or methoxy moiety on the PEC.