Synthesis Of Novel Xanthohumol Analogues And Their Effects On Proliferation And Differentiation Of Osteoblast MC3T3-E1

When osteoclast-dominated bone resorption is greater than osteoblast-dominated bone formation,bone homeostasis is disrupted,leading to osteoporosis.This disease has become another important health problem for the middle-aged and elderly population after diabetes,hypertension and hyperlipidemia.Long-term use of anti-osteoporosis drugs can produce a variety of side effects,ranging from dizziness and nausea to myocardial infarction and cancer.Therefore,in recent years,many domestic and foreign experts and scholars have devoted themselves to exploring new anti-osteoporosis drugs that are safe,effective and can be taken for a long time.Xanthohumol is the main flavonoid in the Chinese herbal medicine hops,and a large number of studies have shown that xanthohumol has anti-cancer,anti-inflammatory,anti-bacterial and anti-osteoporosis effects.Xanthohumol can significantly promote the proliferation of osteoblasts,increase the alkaline phosphatase activity of osteoblasts,and play an important role in the whole process of bone formation from early proliferation and differentiation of osteoblasts to the final mineralization of bone matrix.Therefore,it is of theoretical importance to structurally modify xanthohumol as a lead compound and carry out preliminary studies on the proliferation and differentiation of osteoblasts by new derivatives.Based on the literature research and the previous work of the group,three new derivatives of xanthohumol were designed and synthesized in this thesis:（1）the new derivatives A1～A19 were obtained by replacing the isopentenyl group at the 3’position of the B ring to hydrogen atom and the hydrogen atom at the 5’position with isopentenyl group and modifying the A ring with benzene or other aromatic rings with different substituents;（2）the new derivatives B1～B21 were obtained by replacing the methoxy group at the 6’position of the B ring with hydroxyl group and modifying the A ring to benzene or other aromatic rings with different substituents;（3）the new derivatives C1～C14 were obtained by modifying the isopentenyl group at the 3’position of the B ring to hydrogen atom and modifying the A ring to benzene or other aromatic rings with different substituents.A total of 54 new compounds were synthesized,all of which were structurally confirmed by ¹H NMR,¹³C NMR and HR-MS.The effect of the new derivatives on the proliferation of osteoblasts MC3T3-E1Subclone 14 was evaluated by CCK-8 method,and the results showed that A9,A16,C3,C8,C9,C11,C12 and C14 were stronger than xanthohumol in the proliferation of osteoblasts at 0.2μM concentration.The effect of the new derivatives on osteoblast MC3T3-E1 Subclone 14 differentiation was examined using an alkaline phosphatase kit,and the results showed that A2,A10,B10,B12,B14,B15,B17,B18,B21,C1,C2,C3,C11 and C12 were all more capable of promoting osteoblast differentiation than xanthohumol at 0.2μM concentration.At a concentration of 0.2μM,C11 and C12performed best overall with 109.7±0.9%and 111.3±1.3%on osteoblast proliferation and105.2±1.0%and 115.2±0.6%on alkaline phosphatase activity,respectively.The preliminary results of this thesis laid the foundation for the design and synthesis of new derivatives of xanthohumol and the in-depth study of anti-osteoporosis activity.