Design And Synthesis Of Caffeic Acid Phenethyl Ester Analogues And Study On Their Biological Activity

Caffeic acid phenethyl ester (CAPE) is the main active component of honeybee propoils and possesses many pharmacology activities, such as antibacterial, antivirus, antitumor, anti-oxidative, anti-inflammatory and immunoregulatory activity. Leucopenia is one of hematopathy, caused by antitumor drugs, immunosuppressive agents, chemical materials, radial line and self-immune factor. In the present, colony stimulating factor, granulocyte colony stimulating factor can be applied in the therapy of leucopenia, however, "these drugs are expensive and may induce many side effects, therefore,, it is necessary to find an alternative medicine for leucopenia. A design of CAPE analogues according to the structure and acticity relationship of the known CAPE derivatives, this plays an important roll for its application and development.The anticancer activity and the value of the chemical parameters including hydrophobicity (ClogP), dipole moment, heat of formation, atom charge, highest occupied molecular orbital energy, lowest unoccupied molecular orbital energy and total energy analyzed by the chem3D program MOPAC, we discovered that the anticancer activity increased with the decrease of ClogP. In addition, the anticancer activity increased with the decrease of the total energy. Therefore, in order to increase the activity of CAPE analogues, decrease ClogP and total energy was feasible. According to this rule, we designed two novel CAPE analogues.CAPE and two novel CAPE analogues, (E)-4-hydroxyphenethyl 3-(3,4-dihydroxyphenyl)acrylate (HPDHPA) and (E)-4-nitrophenethyl 3-(3,4-dihydroxyphenyl) acrylate (NPDHPA) were synthesized starting from phenethyl alcohol, p-nitro phenethyl alcohol and p-hydroxyl phenethyl alcohol, prepared by acyl halide reaction. The chemical structure indentified by IR, NMR.The immunoregulatory activity of CAPE and its analogues was researched against the immunosuppressed mice induce by cyclophosphamide, including the white blood cell count, spleen index, thymus index and the level of nitric oxide. The results indicated that the immunoregulatory activity increased at the low dose (3 mg/kg) of HPDHPA and NPDHPA (HPDHPA group> NPDHPA group> CAPE group) and the activity increased with the decrease of ClogP. The immunoregulatory activity was affected by other chemical parameters like total energy, at high dose of the novel CAPE analogues.In order to elucidate the effect of CAPE and its analogues on native immunological system by investigating its effect on cytotoxicity, phagocytosis and nitric oxide production of mouse peritoneal macrophage in vitro. The result of MTT showed that CAPE and its analogues has noncytotoxic to macrophage in the dose of 6.25-50μM. CAPE and NPDHPA can promote phagocytosis of macrophage for neutral red and inhibit NO production of macrophage stimulated by LPS, both in a dose dependent manner.