文章编号:1002-8743(2007)01-0093-06简单香豆素天然产物药理作用与化学结构关系研究进展李锦周1,黄初升2,刘红星2,陈希慧1(1.广西大学化学化工学院,广西南宁530004;2.广西师范学院应用化学研究所,广西南宁530001)摘 要:综述了简单香豆素化合物的天然来源及其具有的抗氧化、抗菌、抗癌等药理作用与其化学结构的关系.关键词:香豆素;药理作用;构效关系中图分类号:O643.32 文献标识码:A香豆素天然产物广泛存在于芸香科、伞形科、菊科、豆科、瑞香科、茄科等高等植物以及动物及微生物代谢产物中[1].迄今,已从自然界生物中分离鉴定的香豆素(I ,coumarin ,2H -1-benzopran -2-one ,苯并(-吡喃酮或1,2-苯并(-吡喃酮)化合物超过1300种[2].对天然产物药理作用的研究是植物药研究关注的一个问题.研究表明,香豆素天然产物具有抗HIV 、抗癌、抗凝血、降压、抗心率失常、抗骨髓疏松、镇痛、抗菌及光敏等广泛的药理活性.其药理作用与化学结构的关系是药物设计的依据之一.近年来,对于简单香豆素、呋喃香豆素和吡喃香豆素天然产物的构效关系研究取得了一定的进展.本文综述简单香豆素天然产物的抗氧化作用、抗菌作用等活性与其化学结构关系的研究进展.1 简单香豆素简单香豆素化合物的结构见II .表1列出了部分从天然植物中分离的该类型的香豆素天然产物.从表1看出,简单的香豆素天然产物的取代基主要有-OH ,-OCH 3,-CH 3,-CHO 等. 研究[2,24]表明,简单香豆素天然产物的药理作用与香豆素母核取代基的种类和取代位置有关.表2给出了一些简单香豆素与活性氧物种作用的试验结果.从表2看出,取代基的种类与取代位对香豆素抗氧活性物种的能力有明显地影响.而简单香豆素抗氧化活性的构效关系在文献[24]中得到进一步的证实(表3).对于4-甲基香豆素衍生物来说,7、8位上有2个-OH 以及-OH 和-NH 2相邻时使香豆素具有强的抗氧化和清除自由基的活性.收稿日期:2006-12-27基金项目:广西自然科学基金项目(桂科自0447002)作者简介:李锦周(1982-),山东临沂人,硕士研究生;陈希慧(1958-),女,博士,教授(chh8858@g xu .edu .cn ).2007年3月 广西师范学院学报(自然科学版)Mar .2007第24卷第1期 Journal of Guangxi Teachers Education University (Natural Science Edition )Vol .24No .1DOI :10.16601/j .cn ki .issn 1001-8743.2007.01.022表1 一些简单香豆素天然产物的植物来源StructureNo .Plant sourceRef .R 3R 4R 5R 6R 7R 81H H H H a ＊H Root of Seseli mairei [3]2H H H H OH H Leaves of Ficus platyphylla [4]3H H CH 3H H H Ethulia vemonioides[5]4H H OCH 3OH OCH 3H Bark o f Frax inus ornus ;Prunus Prostrata [6,7]5H H H OCH 3OH OCH 3Carduumtenuif lorus ;Toonaciliata ;Cyperus in completus [8～10]6H H OCH 3H OCH 3OH ibidibid 7H H H OCH 3OCH 3OH Artemisia subdiguata[11]8HHHOHOCH 3HCarduus tenuiflorus ;Coriandrum [6,8]sativ um ;Fraxinus ornus bark[12]9H H HOCH 3OH H Allamanda doniana roots ;the bark [13]of Xeromphis[14]10H H H H OH OCH 3Zanthoxylum s chinifolium [15]11H H OH H OCH 3OCH 3Artemisia laciniata [16]12H H CHO H H OH fruits of Cnidium monnieri[17]13H H H OH OH H Is odonerio calyx ;aerial of A rtemisia montana [18]14H H H H OH OH Daphne ;Daphne acutiloba [19,20]15H H OH OH OCH 3H Rhamnus disperma[21]16H H H OCH 3OH OH Roots of Jatropha goss y pi folia [22]17H H H OCH 3OCH 3H Artemisia argy i18H H H H OCH 3b ＊Cnidium monnieri (L .)Cuss .19HHOHOCH 3OHc ＊Bupleurum[23]a ＊:OOCCH 3;b ＊:-CH 2CH 2CH (CH 3)2;c ＊:CH 2CH 2C (CH 3)2表2 简单香豆素抗氧活性物种能力的试验结果[2]N amePro antioxidant activity Inhibition of lipid peroxidationScavenging of superox ideInhibition of LT B 4generationInhibitio n of T XB 2g eneration7-hydroxy A nti :++inactiveinactiveinactiveinactivecoumarin 7-methy l Anti :+inactiveinactiveinactiveinactivecoumarin 7-metho xy A nti :++inactiveinactiveinactive53μMcoumarin 7-hydroxy -4-A nti :++inactiveinactiveinactiveinactivemethylcoumarin 7-methoxy -4-Anti :+inactiveinactiveinactive90μM·94 · 广西师范学院学报(自然科学版) 第24卷methylcoumarin 7-hydroxy -6-meth A nti :++inactiveinactiveinactiveinactiveoxy coumarin 6,7-dihy drox y Pro :+13.0(M33.9μM8.3μM>100μMcoumarin 7,8-dihy drox y P ro :++18.0μM10.6μM20μM21μMcoumarin 6,7-d ihydroxy -4-Pro :+8.0μM82.0μM10μMinactivemethylcoumarin 5,7-d ihydroxy -4-Anti :+12.0μMinactiveinactive1μMmethylcoumarin 7,8-d ihydroxy -4-P ro :++2.8μM8.5μM>100μMinactivemethylcoumarin 7,8-d ihydroxy -6-Pro :+++3.3μM5.8μM75μMinactivemethoxy coumarin Antioxidant activity measured in FeCl 3.ascorbate +H 2O 2system ;Pro -oxidant activity measured in FeCl 3.EDTA +H 2O 2system ;Inhibition of lipid pero xidation measured in rat liver microsomal FeCl 3.ascor -bate system ;Scavenging of superoxide radicals measured in human PM N ;Inhibition of generation of LTB 4and TXB 2measured in rat peritoneal leukocytes .文献[25]采用密函理论计算的方法说明香豆素抗氧化活性与其结构的关系.具有邻位双酚结构的香豆素清除自由基以H 原子直接转移的过程为主,而此过程涉及的O -H 解离焓可作为清除自由基活性的指标;对于无邻位双酚结构的香豆素母核,其结构对O -H 解离焓的减少几乎没有积极作用,故其抗氧化能力弱于含邻位双酚结构的香豆素;香豆素母核的B 环(1,2-吡喃酮)是弱吸电子基团,对香豆素的抗氧化活性几乎没有影响.香豆素衍生物的抗真菌、抗血小板聚集与分子结构的关系[15,26,27]亦与取代基种类、数量与位置有关.对于香豆素的抗真菌活性,研究证实4-羟基香豆素无抗真菌活性;香豆素衍生物20,21,22和23全面抑制真菌ATCC 、14053、KF -33、PLM 454的能力与其6-OH 是否有保护基有关;当6-OH 有保护基时,其抗真菌能力明显下降;而对于7-OH ,保护基的存在与否对分子的抗真菌活性没有明显的影响.对于6,7,8-三取代的香豆素化合物,其抗真菌活性与8-取代基的极性有关.表3 几种4-甲基香豆素衍生物的抗氧化能力[24]N ameI nhibition of lipid peroxida -tion a(percent of control )Ridical scavenging (percent o f control )IC 50(μmo l )b4-methyl -7,8-dihydroxy couma -rin1347.94-methyl -7-hy drox y -8-amin -ocoumarin1246.024-methyl -5-amino -6-hydroxy -coumarin 1358.314-methyl -5,7-diamino -6-hy dro xycoumarin16167.12a :Effect of coumarins on NADPH -dependent lipid perox idation in rat liver microsomes ;The inhibitors第1期 李锦周,等:简单香豆素天然产物药理作用与化学结构关系研究进展·95 ·concentration was 100μM .b:The IC50values for inhibition of lipid hydroperoxide form ation ,inhibitors concentration ranging from 0.01to 100μM 香豆素衍生物26抗血小板聚集效果取决于7-取代基的结构[27](Scheme 1),抗血小板聚集活性最高的香豆素7-取代基为Scheme 1中的5.在7-羟基-8-甲氧基-香豆素10和7-香叶氧基-8-甲氧基-香豆素27中,7-位取代基的不同,两者的药理作用不同.27有抗癌作用[33],而10无此作用. 研究[29]表明:4-甲基香豆素(Scheme 2)抗辐射的活性不仅与其芳环的C 是否与烯丙基直接相连密切相关,也与香豆素抗辐射有效结构的极性程度相关.化合物28,29和30显示出高的抗辐射活性,而化合物31和32抗辐射活性很低.对于化合物29来说,7-OH 的H 被-CH 3、-CH 3CO 、C6H 5O -取代后,仍可保持抗辐射的有效基本结构,而6-,7-和8-的取代基的极性太强或太弱,抗辐射活性明显下降.·96 · 广西师范学院学报(自然科学版) 第24卷 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bstract :Natural resource of simple coumarins and the relationship of pharmacological action ,from anti -oxidation ,antifung al ,anticancer ,etc .,to structure is summarized for the coumarins .Key words :coumarins ;pharmacological effect ;structure -activity relationship[责任编辑:黄天放]·98 · 广西师范学院学报(自然科学版) 第24卷。
