摘要
生物体内活性氧是一把双刃剑,既能参与部分生物功能,又能损伤细胞。当体内活性氧过量产生时,会导致癌症、衰老和神经显行性疾病。食品衍生的抗氧化剂能降低许多慢性疾病,特别是癌症的发病率。因此开发及评价高效的抗氧化剂具有十分重要的意义。
本文中,我们合成了多个姜黄素类似物,通过清除DPPH自由基、抑制AAPH诱导的人血红细胞氧化性溶血实验研究了其抗氧化活性及其构效关系；以galvinoxyl和DPPH自由基为氧、氮自由基模型,研究了白藜芦醇类似物、羟基化查尔酮类似物和羟基肉桂酸类似物在不同溶剂中清除自由基的反应动力学,研究了其构效关系,推测了其反应机制；还研究了羟基化查尔酮类化合物抑制AAPH诱导的质粒DNA损伤以及姜黄素类似物Knoevenagel缩合物对人早幼粒白血病细胞HL-60的细胞毒活性。为了进一步阐明不具有对称性的羟基查尔酮化合物的构效关系和反应机制,我们还应用DFT计算了其氧氢键解离焓(BDE)。
实验结果表明：
1)具有邻二羟基和邻二甲氧基羟基结构的姜黄素类似物具有更好的清除DPPH自由基和抑制溶血的活性,并且七个碳结构的该类化合物比五个碳结构的活性好；在五个碳结构的类似物中引入环降低了其清除自由基的活性,却增加了其抑制溶血的活性。说明了化合物亲脂性在抗氧化活性中的重要性。
2)在质子性溶剂(甲醇、乙醇)中,酚类化合物(白藜芦醇及类似物、羟基查尔酮类化合物以及羟基肉桂酸)清除galvinoxyl和DPPH自由基的反应存在质子优先损失的电子转移(SPLET)和氢原子转移(HAT)两种机制,并以SPLET机制为主,而在非质子性溶剂(乙酸乙酯)中则主要是HAT机制；
3)4-OH的邻、对位有羟基、甲氧基等供电子基取代的白藜芦醇类化合物具有更高的抗氧化活性,而引入硝基、三氟甲基等吸电基则降低其活性；
4)酚酸由于其自身的酸性使其在质子性溶剂中的反应速率受阻；
5)对于羟基查尔酮化合物,其实验所得抗氧化结果与其理论计算的氧氢键解离能(BDE)相一致,进一步阐明了其构效关系；
6)姜黄素Knoevenagel缩合物对人早幼粒白血病细胞株(HL-60)的毒活性远强于其母体分子。
ROS (reactive oxygens pecies) have pros and cons for human health. In healthy subject, there is a tightly controlled balance between the generation and removal of ROS. Excissive production of ROS plays an important role in cancer, aging and several degenerative diseases. Plant and food-derived antioxidants have beneficial effect in protecting against these diseases. Thus, development of highly efficient antioxidants has attracted many scientists'attention.
In this article, we synthesized a series of curcumin analogues, studied and compared the capacity of curcumin-directed analogues to scavenge 2,2-diphenyl-l-picrylhydrazyl (DPPH·) and protect human red blood cells (RBCs) from oxidative haemolysis to investigate the structure-activity-relationship; The radical-scavenging activity and detailed mechanism of resveratrol analogues and hydroxyl-chalcones were investigated by the reaction kinetics with galvinoxyl (GO·) and 2,2-diphenyl-l-picrylhydrazyl (DPPH·) radicals in different solvents (ethanol, methanol and ethyl acetate) at 25℃, using UV-vis spectroscopy; Besides, we also examined the activity of hydroxyl-chalcones against free radical (AAPH) mediated DNA strand breakage and curcuminoids Knoevenagel condensates antiproliferative effect on human promyelocytic leukemia cells (HL-60). To interpret the structure-activity-relationship and antioxidant mechanism of hydroxyl-chalcones with the asymmetrical structures, we also calculated O-H bond dissociation enthalpy (BDE).
The results revealed that: 1) The curcumin analogues which bear o-diphenoxyl and o-dimethoxyphenoxyl hydroxyl
groups exhibited significantly higher DPPH·-scavenging and anti-haemolysis activities
than those which bear no such groups. In contrast to curcumin analogues that retained
the 7-carbon spacer, the compounds with a 5-carbon linker had lower activity. In the
case of the latter, the introduction of ring further decreased DPPH·-scavenging activity.
However, the introduction of ring did increase anti-haemolysis activity, suggesting that
the lipophilicity of these compounds might play an important role in the antioxidant
activity. 2) The measured rate constants for radical-scavenging reaction of phenolic antioxidants
(resveratrol analogues, hydroxyl-chalcones as well as hydroxycinnamic acid derivatives) revealed that in supporting ionization solvents (Methanol, ethanol) besides hydrogen atom transfer (HAT), the kinetics of the process was partially governed by sequential proton loss electron transfer (SPLET). The relatively low rate constants for the reactions of ArOHs with radical in ethyl acetate compared with the rate constants in ethanol proved that in ethyl acetate these reactions occured primarily by the HAT mechanism.
3) These compounds of resveratrol analogues, which have electron-donating groups (-OH,-OCH3) in the ortho-or para-position of 4-OH exihibited significantly higher antioxidant activity, but which have electron-withdrawing groups (-NO2,-CF3) exihibited opposite results.
4) Radical-scavenging rate constants of hydroxycinnamic acid derivatives were self-inhibited in methanol for their acidity.
5) The results of hydroxyl-chalcones from experiments were agreed with that from theoretical calculation (BDE), and the structure-activity-relationship analysis was further elucidated.
6) Curcuminods Knoevenagel condensates showed more effective cytotoxicity than the precursor.
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