【摘要】 目的合成具有新结构骨架的含氮姜黄素类抗肿瘤化合物并考察目标化合物的体外抗肿瘤活性。方法以姜黄素和查耳酮为先导物,利用药效团和骨架迁越原理,设计并合成一系列含碱基的姜黄素类似物。选取人肺癌细胞(A-549)和人胃癌细胞(SGC-7901)对所合成的新化合物进行体外抗肿瘤活性筛选。并且用Discovery Studio 2.0软件进行化合物的吸收、分布、代谢和排泄(ADME)预测。结果与结论共合成了15个未见文献报道的新化合物,其结构均经MS(ESI)、1H-NMR确证。体外活性筛选结果表明:所合成的化合物对所测的两种肿瘤细胞的活性明显优于姜黄素。ADME预测结果表明:所合成的化合物都可能在体内被很好地吸收,血浆蛋白结合率较姜黄素有较大提高。更多还原

【Abstract】 Research on new antitumor drugs is of great significance since most of the currently available drugs had the disadvantages of high toxicity,low effection and multidrug resistance against subset of solid tumors.Structure modification of natural products may still deliver new hope for antitumor drug discovery.Curcumin and flavonoids are two kinds of important natural products with antitumor activity for recent years.Based on SAR of curcuminoids and our previous work,15 new novel curcumin analogues were designed and synthesized according to pharmacophore and scaffold hopping principle.Structurally,the new analogues are 1,5-diarylpentadienones which possess one nitrogen-containing substitution at the position 5 on one of the aromatic ring.The target compounds 6a-6n and 6o were obtained using 4-hydroxy-3-methoxybenzaldehyde and 2,4-dihydroxybenzaldehyde as starting materials,respectively.After a series of reactions,and the new compounds were finally obtained via Mannich reaction.The structure of new compounds were confirmed by MS(ESI) and 1H-NMR.All of the new compounds were screened for antiproliferation activity against two human tumor cell lines in vitro.Most of the new analogues showed more potent antiproliferation activitities against both tested cells,than that of curcumin,with IC50 values below 10 μmol · L-1.The substituted groups introduced in the aromatic ring didn’t make significant effect on their activity.The IC50 value of compound 6c and 6b was lower than that of curcumin and chalcone.The results indicated that compounds with alkaline groups,especially morpholine group,resulted in stronger potent activities.Compounds with cyclohexone(6m,6n) showed decreased activities than that with straight carbon chain(6a).Also,compounds with the second alkaline side chain(6h,6k) did not enhance the activities.The compound(6l) introduced a methy group at 4-position obviously resulted in the decreased antitumor activity.In summary,new compounds with five-carbon chain exhibited more potent activities than those with seven-carbon or three-carbon chain.However,substituted groups were introduced at the 4-positon and 2-position resulted in the decreased bioactivities of compounds.And compounds with a chlorine at the 2-position or trifluoromethyl at the 4-position of ring B enhanced antitumor activities.And the’drug-like’ properties predicted by Discovery Studio 2.0 suggested that most of them may be well absorbed by intestine and have good bioavailability.更多还原