Modification Of Curcumin Derivative And Study Of Its Antitumor Activities

Object to design and synthesize C086 derivative C086-1, optimize microwave synthesis conditions, and study the pharmacokinetics of C086-1 in mice and its antitumor activities in vitro and in vivo.Methods 1 Design synthetic route of C086-1, used microwave-assisted and normal method to synthesize C086 derivative C086-1. 2 The synthesized compounds were characterized by 1H NMR spectroscopy and UV spectrum. 3 The microwave-assisted synthesis conditions of C086-1 was optimized from the reaction temperature, reaction time and feed ratio. 4 Pharmacokinetics of C086-1 and C086 was determined respectively by HPLC after intravenous injection in mice. 5 The inhibitory effect of C086-1and C086 on Hep G2, SW620, HL60, MDA-MB-231, K562 tumor cell lines was evaluated by MTT assay. 6 Inhibitory effects of C086-1 and C086 were investigated on the transplantable tumor models in H22 mice.Results 1. TLC analysis showed that microwave-assisted and normal method obtained the same compound, however, microwave-assisted way had many advantages compared to normal method. 2. 1H NMR showed that the synthesized compound is the target C086-1 and ultraviolet spectroscopy showed the maximum absorption peak of the synthesized compound has a blue shift around 330 nm as expected compared to C086.3. Under optimal synthesis conditions, the yield of C086-1 was 27.1%. 4. After intravenously administered the same dose, the pharmacokinetic of C086-1 and C086 were in accordance with open bicameral model. Compared with the C086, C086-1elimination t1/2 did not improved, but AUC(0-∞) was 1.9 times that of the C086. 5.C086-1 could inhibit the proliferation of Hep G2, SW620, HL60, MDA-MB-231 and K562 cell lines in vitro. Although the effect is weaker than C086, MTT assay showed the IC50 value was less than 10μM for Hep G2, SW620 and HL60 after 48 h treatment with C086-1. 6. Results using a H22 tumor xenograft model in mice showed that50mg/kg/d, 100mg/kg/d and 200mg/kg/d administrated intravenously C086-1respectively obtain tumor inhibition rates of 18.11%, 43.52%, 34.62%, while 200mg/kg/d administrated intravenously C086 only reached an inhibition rate of34.41%.Conclusions 1. Design and synthesis C086 derivative C086-1, 1H NMR and UV spectra showed that the synthesized compound was C086-1. Compared to normal method, microwave- assisted way had many advantages, Under optimal synthesis conditions, the yield of C086-1 was 27.1%. 2. A HPLC analytical method was established for the determination of C086-1 in plasma, the method was accurate, reliable and easy to operate.Intravenously administered the same dose of drugs, bioavailability of C086-1was higher than the nucleus C086. 3. C086-1 can inhibit the proliferations of different tumor cell lines. Although the effect is weaker than C086, MTT assay showed the IC50 value was less than 10μM for Hep G2, SW620 and HL60 after 48 h treatment with C086-1. 4. C086-1 had a certain extent inhibition on the growth of H22 mice xenograft tumor after intravenous administration,and in the anti-tumor activity of C086-1 was higher than C086.