厚朴酚与和厚朴酚衍生物的合成、表征及体外抗炎及抗肿瘤活性评价

Synthesis and characterization of magnolol and honokiol derivatives and evaluation of their anti-inflammatory and anti-tumor activities in vitro

厚朴酚与和厚朴酚是天然产物中的活性单体,在抗炎和抗肿瘤增殖方面表现出优异的药理活性,但其细胞毒性限制了它们的应用。这促使研究者们对其进行结构修饰,以期降低其细胞毒性且保持甚至提高药理活性。本研究对厚朴酚与和厚朴酚的酚羟基进行修饰,通过引入酯基、酰肼、1,3,4-噁二唑等结构,合成了6个衍生物,其中5个衍生物为首次报道,并通过UV、IR、MS、NMR分析与晶体结构对6个衍生物进行了结构表征和绝对构型的确定。对所得衍生物进行了体外细胞毒性、抗炎和抗肿瘤活性评价。结果显示,所得衍生物对小鼠巨噬细胞(RAW264.7)细胞毒性较原型药物显著降低,可在不同程度上抑制炎症介质NO、IL-1β和TNF-α的产生,可有效抑制人乳腺癌(MCF-7)、人肝癌(HepG2)、人非小细胞肺癌(H1299、A549)的增殖。综上所述,本研究为天然产物的减毒增效衍生化设计提供了一定的参考价值。

Magnolol and honokiol,an active monomer from natural products,have shown superior pharmacological activities in anti-inflammation and anti-tumor proliferation,but the cytotoxicity limits their use.It prompted researchers to modify its structure to reduce the cytotoxicity while maintaining or even increasing the efficacy.Six derivatives were synthesized by introducing ester group,acylhydrazide and 1,3,4-oxadiazole at phenolic hydroxyl groups of magnolol and honokiol,of which five derivatives were synthesized for the first time.The structures of six compounds were analyzed by UV,IR,MS,NMR,and the absolute configurations of honokiol ester were determined according to the crystal structure.The in vitro cytotoxicity,anti-inflammatory and anti-tumor activities of derivatives were evaluated.It showed that the cytotoxicitiy of derivatives were significantly reduced when compared with magnolol and honokiol,the inflammatory mediators NO,IL-1β,and TNF-αwere also inhibited by the derivatives,the anti-tumor research revealed antiproliferative effects of derivatives on human breast cancer(MCF-7),human hepatoma(HepG2)and human NSCLC(H1299,A549).In conclusion,this study provides certain reference values on structure modification of natural products for reducing cytotoxicity and improving pharmacological activities.