片叶苔素D药动学、质量控制及衍生物的合成研究
|
摘要
1.立题背景
片叶苔素D是从中国苔类植物Dumortiera hirsute中分离得到的双联苄类化合物。生物活性研究显示,片叶苔素D在体内外均有良好的抗真菌、抗肿瘤活性。抗真菌方面,片叶苔素D通过下调菌丝特异基因,从而抑制菌丝生长,影响生物膜形成,对白色念珠菌产生较好的抗真菌活性,更引人注意的是片叶苔素D对氟康唑耐药菌株表现相同的抗真菌活性,提示片叶苔素D是一个潜在的抗真菌剂；抗肿瘤方面,片叶苔素D与已进入临床阶段的抗肿瘤药Combrastatin A4结构相似,均属于联苄类化合物,提示它可能的抗肿瘤活性。体外研究发现,片叶苔素D通过抑制微管蛋白形成、抑制肿瘤血管生长等方式对KB、MCF-7、PC3等多个肿瘤细胞系产生抑制作用；在体内,片叶苔素D对人白血病细胞HL-60产生明显抑制作用,但对相应的拓扑异构酶Ⅱ缺乏的HL-60/MX2细胞无明显抑制作用,说明片叶苔素D可选择性抑制拓扑异构酶Ⅱ活性,与己上市的抗肿瘤药、拓扑异构酶Ⅱ抑制剂etoposide(依托泊苷,表鬼臼毒吡喃葡萄糖苷)相比,对拓扑异构酶Ⅱ有更强的抑制作用；通过将人肺癌细胞H460注入小鼠体内的方式,建立肺癌小鼠模型,连续三周以20mg/Kg的剂量尾静脉注射片叶苔素D,对照组静注相同剂量etoposide,结果显示,片叶苔素D抑瘤作用与etoposide相当,且毒性远低于etoposide,无明显毒性。根据体内外研究结果,提示片叶苔素D可能是一种新型的拓扑异构酶Ⅱ抑制剂,且毒性小于已上市的拓扑异构酶Ⅱ抑制剂etoposide,说明其具有良好的开发前景,目前课题组已完成片叶苔素D的全合成研究；针对片叶苔素D水溶性差,可能引起的口服生物利用度低的问题,开展了片叶苔素D纳米晶体的研究。
为进一步推动新药研究,有必要对片叶苔素D进行药代动力学、体内组织分布、排泄特点及体内代谢方式及代谢产物进行研究,为新药的设计和开发工作提供药动学信息；通过研究片叶苔素D在体外对P450酶的抑制作用,预测它与其他药物间可能的相互作用；研究片叶苔素D的质量控制方法并形成质量标准草案,完善片叶苔素D作为候选药物的前期研究工作。
2.片叶苔素D代谢产物合成研究
初步完成片叶苔素D葡萄糖苷的合成研究,为下一步片叶苔素D制剂药动学研究中片叶苔素D体内代谢产物对照品的制备打下基础,也为同类化合物的合成打下基础。
3.片叶苔素D药动学、组织分布及排泄研究
建立了快速测定灌胃给药和静脉注射给药后大鼠血浆、各组织、排泄物中片叶苔素D原型的HPLC\MS\MS方法,并通过葡萄糖醛酸酶水解法测定了血浆及排泄物中片叶苔素D总量(原型加结合型),并计算出相关药动学参数。经专一性、基质效应、绝对回收率、相对回收率、精密度、准确度及稳定性等确证建立的方法可用于生物样本中片叶苔素D原型药及总量测定；药动学结果显示,片叶苔素D口服给药后生物利用度较低,分别为：给药剂量为20mg/Kg时,生物利用度为13.4%,给药剂量为40mg/Kg时,生物利用度为6.2%,给药剂量为80mg/Kg时,生物利用度为9.8%；按酶水解后片叶苔素D的总量计算,片叶苔素D总量的口服生物利用度分别为：给药剂量为20mg/Kg时,生物利用度为23.2%,给药剂量为40mg/Kg时,生物利用度为24.0%,给药剂量为80mg/Kg时,生物利用度为21.6%,即相同给药剂量时片叶苔素D总量生物利用度高于原型药,提示片叶苔素D吸收过程中可能发生较强的首过代谢而形成结合型代谢产物；组织分布研究显示,口服给药后,片叶苔素D除在胃、小肠等消化道组织有较高浓度外,在其他组织分布浓度均较低；静注给药后,片叶苔素D在各组织中分布广泛,尤其在肺中浓度较高,但在各组织消除迅速；静脉及灌胃给药后,片叶苔素D原型药主要经粪便排泄；片叶苔素D结合型主要经胆汁排泄；尿样中原型药及结合型均较少；体内代谢分析显示,片叶苔素D体内代谢产物主要为片叶苔素D结合一分子葡萄糖醛酸的Ⅱ相代谢产物,且互为异构体；核磁共振波谱分析结合片叶苔素D的结构特点,推断两个异构体为旋阻异构;两个异构体在室温下存在相互转化,直至达到约为1：1的比例。
4.片叶苔素D P450酶体外抑制活性
采用荧光法、高通量P450酶抑制剂筛选试剂盒,测定片叶苔素D对人同工酶CYP1A2、CYP2C19及CYP3A4的抑制活性,片叶苔素D对CYP1A2活力抑制的IC5d>20μM,基本无抑制作用(IC50>10μM),对CYP2C19活力抑制作用IC50与相应阳性对照药物基本一致,对CYP3A4活力抑制作用IC50较相应阳性药物高,但仍属于有抑制作用。
5.片叶苔素D质量控制方法研究
研究片叶苔素D质量控制方法,通过方法学研究,确定片叶苔素D性状外观、溶解度、鉴别、检查及含量测定方法并制定质量标准草案。建立片叶苔素D红外及高效液相色谱鉴别方法；高效液相色谱法测定片叶苔素D有关物质及含量；气相色谱法测定片叶苔素D残留溶剂。
6.总结与展望
片叶苔素D因其良好的体内外生物活性,尤其是机制较为清晰的抗肿瘤活性、较低的毒性而具有良好的开发前景。
本文通过建立快速、灵敏、选择性好的HPLC-MS/MS方法测定血浆及十种组织中片叶苔素D的含量,经方法学确证能满足测定要求；准确描述片叶苔素D在体内药代动力学特征、组织分布、排泄情况,为其进一步结构修饰及剂型开发提供药动学科学依据：为克服较强的首过效应,提高其药效,应在进一步研究中关注片叶苔素D的结构修饰、筛选适宜的的剂型；因片叶苔素D水中几乎不溶,导致其口服生物利用度低,限制其应用,故应在目前课题组已开展的片叶苔素D纳米晶体研究的基础上,作进一步研究,以提高其溶解度；静注结果显示片叶苔素D在肺部有较多分布,与片叶苔素D体内活性结果相符,提示片叶苔素D在治疗肺癌方面具有可开发性；片叶苔素D体内外代谢物和代谢途径的研究发现片叶苔素D的体内代谢产物为Ⅱ相葡萄糖醛酸结合产物,确证其结构,有针对性地开展合成研究工作,为制剂研究中片叶苔素D结合型的测定中对照品的制备打下物质基础并且为今后该类化合物的合成打下基础；初次考察了片叶苔素D对某些P450同工酶的抑制作用,为今后片叶苔素D与其他药物或食物同用时可能的相互作用作出预测；完成片叶苔素D质量研究工作,完善片叶苔素D新药研究的前期工作。
1. Research background
Riccardin D, a macrocyclic bisbibenzy extracted from Chinese liverworts Dumortiera hirsute, has been shown to have antifungal and anticancer activities both in vitro and in vivo. For antifungal activity, Riccardin D interfered with the biofilm formation of Candida albicans through downregulating the expression of hyphase specific genes and inhibiting the formation of hyphase and exhibited antifungal activity against Candida albicans, and also found to reverse fungal resistance to flueonazole by increasing aecumulation of flueonazole in the Calbieans. For anticancer activity, in vitro, RD exhibited cytotoxic effects against multiple cancer cell lines, such as KB, MCF-7, PC3, and human lung carcinoma cells via multiple mechanisms including anti-tubulin, antiangiogenic effects. Riccardin D had a significant antiproliferative effect on human leukemia cell lines HL-60, but showed no effect on the topoisomerase-Ⅱ-deficient HL-60/MX2cells. The pBR322DNA relaxation assay revealed that riccardin D selectively inhibited the activity of topoisomerase Ⅱ and the susppression of topoisomerase Ⅱ activity by riccardin D was stronger than that of etoposide, a known topoisomerase Ⅱ inhibitor. In vivo, RD exhibited significant inhibitory effects on the growth of human NSCLC tumors in a xenograft mouse model and APCmin/+model, the inhibitory effects by riccardin D was similar to etoposide but without obvious toxicity to animals after three weeks injection. Although accumulating evidence demonstrate that riccardin D is a novel NDA topoisomerase Ⅱ inhibitor and considered as a potential candidate compound for treatment of cancers, the pharmacokinetic studies, a critical component in drug development process, are missing. Herein, we investigated the absorption, metabolism, tissue distribution and excretion of RD in rats to provide valuable pharmacokinetic information to facilitate the development of RD as an anticancer drug.
2. Synthesis of riccardin D's metabolite
The metabolite of riccardin D was synthesized and the structure was confirmed by HPLC\MS via compared with that in bile samples.
3. The absorption,distribution,metabolism,and excretion of Riccardin D in rats
The present study was designed to investigate the pharmacokinetics following oral and intravenous administration of Riccardin D, an anticancer drug candidate isolated from Chinese liverworts Dumortiera hirsute, in Wistar rats. An HPLC-MS/MS analytical method was developed and validated. The results demonstrated that Riccardin D's bioavailability was13.4%,11.4%, and9.8%after oral administration at20mg/Kg,40mg/Kg, and80mg/Kg, respectively. There was no significant difference in the elimination half-time of Riccardin D at these doses, suggesting that Riccardin D may have linear pharmacokinetic characteristics in rats. The metabolite of Riccardin D in rat was identified as the glucuronide of Riccardin D. Riccardin D showed a wide distribution in various tissues followed by a rapid elimination from most of the tissues tested. Riccardin D was found to distribute widely in the tissues0.5h after oral and intravenous administration. The tissue concentrations were markedly decreased8h and6h after oral and intravenous dosing, respectively. Both Riccardin D and its conjugated metabolite were detected in urine and bile samples while only Riccardin D was detected in feces. The metabolite and metabolic pathway of riccardin D in vivo was studied. In vivo, rat biles were collected after administration of riccardin D and were analysized by HPLC-MSn method after disposition. the metabolite of riccardin D in rat was identified as the glucuronide conjugate of riccardin D for the first time. Taken together, the study provided valuable pharmacokinetic data for further drug development of Riccardin D.
4. P450inhibition activity
CYPs(CYP1A2,CYP2C19,CYP3A4) high throughput inhibitor screening kit were used and the methods were validated by their positive control inhibitors. The IC50was over20μM to CYP1A2,2.83μM to CYP2C19and1.70μM to CYP3A4.
5. The study on the riccardin D's quality control
The method of riccardin D's quality control was studied and the standard was established.
6. Conclusion and prospect
The HPLC-MS/MS method was simple, rapid and sensitive enough to meet the requirements for the quantitation of riccardin D in biology samples.
Riccardin had a low oral bioavailability, which limits its development. The study to prepare the nanocrystals to enhance its dissolution is undergoing.
Riccardin D shows a wide distribution in various tissues followed by a rapid elimination from most of these tissues. After intravenous administration, Riccardin D had a higher content in lung. Therefore it has potential to be a lung cancer inhibitor. This is in accordance with the previous study showing that RD had promising inhibitory effect on human lung cancer cells in vitro and in NSCLCH460xenografts bearing mouse mode. The results of metabolism study in vivo demonstrated that riccardin D's metabolite was the conjugate with glucuronate of phase II metabolism and was identified as a mixture of two enantiomeric atropisomers. The synthesis of the conjugate is undergoing and the synthesized conjugate will be useful in further study on riccardin D preparation's pharmacokinetics. Riccardin D has no inhibitory action to CYP1A2but has inhibitory action to CYP2C19and CYP3A4. The established standard can be used for the quality control of riccardin D.
片叶苔素D是从中国苔类植物Dumortiera hirsute中分离得到的双联苄类化合物。生物活性研究显示,片叶苔素D在体内外均有良好的抗真菌、抗肿瘤活性。抗真菌方面,片叶苔素D通过下调菌丝特异基因,从而抑制菌丝生长,影响生物膜形成,对白色念珠菌产生较好的抗真菌活性,更引人注意的是片叶苔素D对氟康唑耐药菌株表现相同的抗真菌活性,提示片叶苔素D是一个潜在的抗真菌剂；抗肿瘤方面,片叶苔素D与已进入临床阶段的抗肿瘤药Combrastatin A4结构相似,均属于联苄类化合物,提示它可能的抗肿瘤活性。体外研究发现,片叶苔素D通过抑制微管蛋白形成、抑制肿瘤血管生长等方式对KB、MCF-7、PC3等多个肿瘤细胞系产生抑制作用；在体内,片叶苔素D对人白血病细胞HL-60产生明显抑制作用,但对相应的拓扑异构酶Ⅱ缺乏的HL-60/MX2细胞无明显抑制作用,说明片叶苔素D可选择性抑制拓扑异构酶Ⅱ活性,与己上市的抗肿瘤药、拓扑异构酶Ⅱ抑制剂etoposide(依托泊苷,表鬼臼毒吡喃葡萄糖苷)相比,对拓扑异构酶Ⅱ有更强的抑制作用；通过将人肺癌细胞H460注入小鼠体内的方式,建立肺癌小鼠模型,连续三周以20mg/Kg的剂量尾静脉注射片叶苔素D,对照组静注相同剂量etoposide,结果显示,片叶苔素D抑瘤作用与etoposide相当,且毒性远低于etoposide,无明显毒性。根据体内外研究结果,提示片叶苔素D可能是一种新型的拓扑异构酶Ⅱ抑制剂,且毒性小于已上市的拓扑异构酶Ⅱ抑制剂etoposide,说明其具有良好的开发前景,目前课题组已完成片叶苔素D的全合成研究；针对片叶苔素D水溶性差,可能引起的口服生物利用度低的问题,开展了片叶苔素D纳米晶体的研究。
为进一步推动新药研究,有必要对片叶苔素D进行药代动力学、体内组织分布、排泄特点及体内代谢方式及代谢产物进行研究,为新药的设计和开发工作提供药动学信息；通过研究片叶苔素D在体外对P450酶的抑制作用,预测它与其他药物间可能的相互作用；研究片叶苔素D的质量控制方法并形成质量标准草案,完善片叶苔素D作为候选药物的前期研究工作。
2.片叶苔素D代谢产物合成研究
初步完成片叶苔素D葡萄糖苷的合成研究,为下一步片叶苔素D制剂药动学研究中片叶苔素D体内代谢产物对照品的制备打下基础,也为同类化合物的合成打下基础。
3.片叶苔素D药动学、组织分布及排泄研究
建立了快速测定灌胃给药和静脉注射给药后大鼠血浆、各组织、排泄物中片叶苔素D原型的HPLC\MS\MS方法,并通过葡萄糖醛酸酶水解法测定了血浆及排泄物中片叶苔素D总量(原型加结合型),并计算出相关药动学参数。经专一性、基质效应、绝对回收率、相对回收率、精密度、准确度及稳定性等确证建立的方法可用于生物样本中片叶苔素D原型药及总量测定；药动学结果显示,片叶苔素D口服给药后生物利用度较低,分别为：给药剂量为20mg/Kg时,生物利用度为13.4%,给药剂量为40mg/Kg时,生物利用度为6.2%,给药剂量为80mg/Kg时,生物利用度为9.8%；按酶水解后片叶苔素D的总量计算,片叶苔素D总量的口服生物利用度分别为：给药剂量为20mg/Kg时,生物利用度为23.2%,给药剂量为40mg/Kg时,生物利用度为24.0%,给药剂量为80mg/Kg时,生物利用度为21.6%,即相同给药剂量时片叶苔素D总量生物利用度高于原型药,提示片叶苔素D吸收过程中可能发生较强的首过代谢而形成结合型代谢产物；组织分布研究显示,口服给药后,片叶苔素D除在胃、小肠等消化道组织有较高浓度外,在其他组织分布浓度均较低；静注给药后,片叶苔素D在各组织中分布广泛,尤其在肺中浓度较高,但在各组织消除迅速；静脉及灌胃给药后,片叶苔素D原型药主要经粪便排泄；片叶苔素D结合型主要经胆汁排泄；尿样中原型药及结合型均较少；体内代谢分析显示,片叶苔素D体内代谢产物主要为片叶苔素D结合一分子葡萄糖醛酸的Ⅱ相代谢产物,且互为异构体；核磁共振波谱分析结合片叶苔素D的结构特点,推断两个异构体为旋阻异构;两个异构体在室温下存在相互转化,直至达到约为1：1的比例。
4.片叶苔素D P450酶体外抑制活性
采用荧光法、高通量P450酶抑制剂筛选试剂盒,测定片叶苔素D对人同工酶CYP1A2、CYP2C19及CYP3A4的抑制活性,片叶苔素D对CYP1A2活力抑制的IC5d>20μM,基本无抑制作用(IC50>10μM),对CYP2C19活力抑制作用IC50与相应阳性对照药物基本一致,对CYP3A4活力抑制作用IC50较相应阳性药物高,但仍属于有抑制作用。
5.片叶苔素D质量控制方法研究
研究片叶苔素D质量控制方法,通过方法学研究,确定片叶苔素D性状外观、溶解度、鉴别、检查及含量测定方法并制定质量标准草案。建立片叶苔素D红外及高效液相色谱鉴别方法；高效液相色谱法测定片叶苔素D有关物质及含量；气相色谱法测定片叶苔素D残留溶剂。
6.总结与展望
片叶苔素D因其良好的体内外生物活性,尤其是机制较为清晰的抗肿瘤活性、较低的毒性而具有良好的开发前景。
本文通过建立快速、灵敏、选择性好的HPLC-MS/MS方法测定血浆及十种组织中片叶苔素D的含量,经方法学确证能满足测定要求；准确描述片叶苔素D在体内药代动力学特征、组织分布、排泄情况,为其进一步结构修饰及剂型开发提供药动学科学依据：为克服较强的首过效应,提高其药效,应在进一步研究中关注片叶苔素D的结构修饰、筛选适宜的的剂型；因片叶苔素D水中几乎不溶,导致其口服生物利用度低,限制其应用,故应在目前课题组已开展的片叶苔素D纳米晶体研究的基础上,作进一步研究,以提高其溶解度；静注结果显示片叶苔素D在肺部有较多分布,与片叶苔素D体内活性结果相符,提示片叶苔素D在治疗肺癌方面具有可开发性；片叶苔素D体内外代谢物和代谢途径的研究发现片叶苔素D的体内代谢产物为Ⅱ相葡萄糖醛酸结合产物,确证其结构,有针对性地开展合成研究工作,为制剂研究中片叶苔素D结合型的测定中对照品的制备打下物质基础并且为今后该类化合物的合成打下基础；初次考察了片叶苔素D对某些P450同工酶的抑制作用,为今后片叶苔素D与其他药物或食物同用时可能的相互作用作出预测；完成片叶苔素D质量研究工作,完善片叶苔素D新药研究的前期工作。
1. Research background
Riccardin D, a macrocyclic bisbibenzy extracted from Chinese liverworts Dumortiera hirsute, has been shown to have antifungal and anticancer activities both in vitro and in vivo. For antifungal activity, Riccardin D interfered with the biofilm formation of Candida albicans through downregulating the expression of hyphase specific genes and inhibiting the formation of hyphase and exhibited antifungal activity against Candida albicans, and also found to reverse fungal resistance to flueonazole by increasing aecumulation of flueonazole in the Calbieans. For anticancer activity, in vitro, RD exhibited cytotoxic effects against multiple cancer cell lines, such as KB, MCF-7, PC3, and human lung carcinoma cells via multiple mechanisms including anti-tubulin, antiangiogenic effects. Riccardin D had a significant antiproliferative effect on human leukemia cell lines HL-60, but showed no effect on the topoisomerase-Ⅱ-deficient HL-60/MX2cells. The pBR322DNA relaxation assay revealed that riccardin D selectively inhibited the activity of topoisomerase Ⅱ and the susppression of topoisomerase Ⅱ activity by riccardin D was stronger than that of etoposide, a known topoisomerase Ⅱ inhibitor. In vivo, RD exhibited significant inhibitory effects on the growth of human NSCLC tumors in a xenograft mouse model and APCmin/+model, the inhibitory effects by riccardin D was similar to etoposide but without obvious toxicity to animals after three weeks injection. Although accumulating evidence demonstrate that riccardin D is a novel NDA topoisomerase Ⅱ inhibitor and considered as a potential candidate compound for treatment of cancers, the pharmacokinetic studies, a critical component in drug development process, are missing. Herein, we investigated the absorption, metabolism, tissue distribution and excretion of RD in rats to provide valuable pharmacokinetic information to facilitate the development of RD as an anticancer drug.
2. Synthesis of riccardin D's metabolite
The metabolite of riccardin D was synthesized and the structure was confirmed by HPLC\MS via compared with that in bile samples.
3. The absorption,distribution,metabolism,and excretion of Riccardin D in rats
The present study was designed to investigate the pharmacokinetics following oral and intravenous administration of Riccardin D, an anticancer drug candidate isolated from Chinese liverworts Dumortiera hirsute, in Wistar rats. An HPLC-MS/MS analytical method was developed and validated. The results demonstrated that Riccardin D's bioavailability was13.4%,11.4%, and9.8%after oral administration at20mg/Kg,40mg/Kg, and80mg/Kg, respectively. There was no significant difference in the elimination half-time of Riccardin D at these doses, suggesting that Riccardin D may have linear pharmacokinetic characteristics in rats. The metabolite of Riccardin D in rat was identified as the glucuronide of Riccardin D. Riccardin D showed a wide distribution in various tissues followed by a rapid elimination from most of the tissues tested. Riccardin D was found to distribute widely in the tissues0.5h after oral and intravenous administration. The tissue concentrations were markedly decreased8h and6h after oral and intravenous dosing, respectively. Both Riccardin D and its conjugated metabolite were detected in urine and bile samples while only Riccardin D was detected in feces. The metabolite and metabolic pathway of riccardin D in vivo was studied. In vivo, rat biles were collected after administration of riccardin D and were analysized by HPLC-MSn method after disposition. the metabolite of riccardin D in rat was identified as the glucuronide conjugate of riccardin D for the first time. Taken together, the study provided valuable pharmacokinetic data for further drug development of Riccardin D.
4. P450inhibition activity
CYPs(CYP1A2,CYP2C19,CYP3A4) high throughput inhibitor screening kit were used and the methods were validated by their positive control inhibitors. The IC50was over20μM to CYP1A2,2.83μM to CYP2C19and1.70μM to CYP3A4.
5. The study on the riccardin D's quality control
The method of riccardin D's quality control was studied and the standard was established.
6. Conclusion and prospect
The HPLC-MS/MS method was simple, rapid and sensitive enough to meet the requirements for the quantitation of riccardin D in biology samples.
Riccardin had a low oral bioavailability, which limits its development. The study to prepare the nanocrystals to enhance its dissolution is undergoing.
Riccardin D shows a wide distribution in various tissues followed by a rapid elimination from most of these tissues. After intravenous administration, Riccardin D had a higher content in lung. Therefore it has potential to be a lung cancer inhibitor. This is in accordance with the previous study showing that RD had promising inhibitory effect on human lung cancer cells in vitro and in NSCLCH460xenografts bearing mouse mode. The results of metabolism study in vivo demonstrated that riccardin D's metabolite was the conjugate with glucuronate of phase II metabolism and was identified as a mixture of two enantiomeric atropisomers. The synthesis of the conjugate is undergoing and the synthesized conjugate will be useful in further study on riccardin D preparation's pharmacokinetics. Riccardin D has no inhibitory action to CYP1A2but has inhibitory action to CYP2C19and CYP3A4. The established standard can be used for the quality control of riccardin D.
引文
[1]YL. Qiu, J. D. Palmer, Trends Plant Sci.,1999,4,26-30.
[2]衣艳君,中国药用苔藓植物资源[J].中草药,2000,31(08)：624-628.
[3]Asakawa Y, Ludwiczuk A, Nagashima F. Phytochemical and biological studies of bryophytes[J]. Phytochemistry.2012 May 29(In press).
[4]Asakawa. Y.. Chemosystematics of the Hepaticae[J]. Phytochemistry,2004, 65(6):623-669.
[5]Asakawa, Y.. Biologically active compounds from bryophytes[J]. Pure and Applied Chemistry,2007,79,557-580.
[6]Harinantenaina,L.,Quang,D.N., Takeshi,N., Hashimoto,T.,Kohchi,C.:Soma, J.I., Asakawa,Y. Bis(bibenzyls) from liverworts inhibit lipopolysaccharide-induced inducible NOS in RAW 264.7 cells:a study of structure-activity relationships and molecular mechanism[J].J Nat. Prod.,2005,68(12):1779-81
[7]Seung-Hwa Baek, Richard K. Phipps,Nigel B. Perry. Antimicrobial Chlorinated Bibenzyls from the Liverwort Riccardia marginata[J]. J. Nat. Prod.2004, 67(4):718-720
[8]Labbe C, Faini F, Villagran C, Coll J, Rycroft DS. Bioactive polychlorinated bibenzyls from the liverwort Riccardia polyclada[J]. J Nat Prod.2007,70(12):2019-21.
[9]Asakawa, Y. Chemical constituents of the Bryophytes. In W. Herz, E. W. Kirby, R. E. Moore, W. Steglich, & Ch. Tamm, Progress in the Chemistry of Organic Natural Products,1995,65,1-618
[10]Hermann Anton, Ralph Schoeneborn, Ruediger Mues. Bibenzyls and bisbibenzyls from a neotropical Plagiochila species[J]. Phytochemistry 1999,52(8):1639-1645
[11]Dadid S.,W. John Cole, Nadia Aslam. Bibenzyls and bisbibenzyls from a neotropical Plagiochila species[J]. Phytochemistry,1998,49(1):145-148
[12]Stephan H.,Wilfried A.,Konig. A.2-arylbenzofurans of presumed stilbenoid origin from Corsinia coriandrina (Hepaticae)[J]. Phytochemistry,2004,23(65):3113-3118
[13]Hermann Anton,Ludwig Kraut, Rijdiger Muest, Mariai Morales Z. Phenznthrenes and Bibenzyls From a Plagiochila Species[J].Phytochemistry,1997,46(6):1069-1075
[14]Frank Cullamnn, Hans Becker,Enriqlje Pandolfi, et al. Bibenzyl Derivatives From PELLIA EPIPHYLLA[J].Phytochemistry,1997,45(6):1235-1247
[15]Joseph D.Connollya,David S.Rycrofta,Dharmatma L., et al. Aromatic compounds from the liverwort Plagiochila spinulos[J]. Phytochemistry,1999,50(7):1159-1165
[16]Pei-Lin Wu,Yu-Lin Hsu, Chen-Wei Zao, et al.Constituents of Vittaria anguste-elongata and Their Biological Activities[J]. J. Nat. Prod.2005,68(8): 1180-1184
[17]Alicia Bardona, Graciela Bovi Mitrea, Norma Kamiyaa, et al. Eremophilanolides and other constituents from the Argentine liverwort Frullania brasiliensis[J].Phytochemistry,2002,59(2),205-213
[18]Ronlan, A., Hammerich, O., Parker, V.D.. Anodic oxidation of methoxybibenzyls. Products and mechanism of the intramolecular cyclization[J]. Journal of the American Chemical Society,1973,95:7132-7138.
[19]Siegmund Kunz, Hans Becker. Bibenzyl derivatives from the liverwort Ricciocarpos natans[J].Phytochemistry,1994,36(3),675-677
[20]Zhang,G.N., Zhang,C.F., Wang,Z.T., Xu,L.S.. Studies on Chemical Constituents of Dendrobium thyrsiflorum Rchb.f [J]Chin. J. Nat. Med.,2004,2:78
[21]Hermann Anton,Ludwig Kraut, Rijdiger Muest, Mariai Morales Z. Phenznthrenes and Bibenzyls From a Plagiochila Species[J].Phytochemistry,1997,46(6):1069-1075
[22]Lou HX, Li GY,Wang FQ.A cytotoxic diterpenoid and antifungal phenolic compounds from Frullania muscicola Steph[J]. J Asian Nat Prod Res.2002,4(2): 87-94.
[23]Yoshida,T., Hashimoto,T., Takaoka,S., et al. Phenolic constituents of the liverwort:Four novel cyclic bisbibenzyl dimers from Blasia pusilla LOriginal Research Article[J].Tetrahedron,1996,52(46):14487.
[24]Nagashima F, Toyota M, Asakawa Y. Bazzanane sesquiterpenoids from the New Zealand liverwort Frullania falciloba[J]. Chem Pharm Bull.2006;54(9):1347-9.
[25]Ludwig Kraut, Riidiger Mues, Hans Dietmar Zinsmeister. Prenylated bibenzyl derivatives from Lethocolea glossophylla and Radula volute[J]. Phytochemistry,1997,45(6) 1249-1255
[26]Daniela M. Biondi, Concetta Rocco, Giuseppe Ruberto. New Dihydrostilbene Derivatives from the Leaves of Glycyrrhiza glabra and Evaluation of Their Antioxidant Activity[J]. J. Nat. Prod.2003,66(4):477-480
[27]Samneang Apisantiyakom, Prasat Kittakoop, Thanaporn Manyuma, et al. Novel Biologically Active Bibenzyls from Bauhinia saccocalyx PIERRE[J]. Chem. Biodiv.,2004,1(11):1694
[28]Biondi,D.M., Roeeo,C., Ruberto,G.J. Dihydrostilbene derivatives from Glycyrrhiza glabra leaves[J].Nat.Prod.,2005,68(7):1099-102
[29]Hermann Anton, Ludwig Kraut, Rijdiger Muest, et al.Z. Phenznthrenes and Bibenzyls From a Plagiochila Species[J].Phytochemistry,1997,46(6):1069-1075
[30]Masao Toyota, Tomohide Kinugawa, Yoshinoiu Asakawa. Bibenzyl cannabinoid and bisbibenzyl derivative from the liverwort Radula perrottetii[J]. Bibenzyl cannabinoid and bisbibenzyl derivative from the liverwort Radula perrottetii[J]. Phytochemistry,1994,37(3):859-862
[31]Masao Toyota, Eri Nakaishi, Yoshinori Asakaw. Eudesmane-type sesquiterpenoids from the liverwort Lepidozia vitreaOrigina[J]. Photochemistry, 1996,41(3):833-836.
[32]Nagashima F, Kuba Y, Asakawa Y. Diterpenoids and aromatic compounds from the three New Zealand liverworts Jamesoniella kirkii, Balantiopsis rosea, and Radula species[J]. Chem Pharm Bull (Tokyo).2006 Jun;54(6):902-6.
[33]Qu JB, Xie CF, Ji M, et al. Water-soluble constituents from the Liverwort Marchantia polymorpha [J]. Helv Chim Acta,2007,90:2109-2115.
[34]Siegmund Kunz, Hans Becker Bibenzyl glycosides from the liverwort Ricciocarpos natans[J].Phytochemistry,1992,31(11):3981-3983
[35]Sianne Schwikkard, Bing-Nan Zhou, Thomas E. Glass, et al. Bioactive Compounds from Combretum erythrophyllum[J].J. Nat. Prod.2000,63(4):457-460
[36]HAN Guang-Xuan, WANG Li-Xin, ZHANG Wei-Dong, et al. Studies on chemical constituents of Bletilla striata(Ⅱ)[J] Acad. J. Sec. Mil. Med. Univ.,2002,23(9):1029-1031
[37]Ki Yong Lee, Sang Hyun Sung, Young Choong Kim. Neuroprotective Bibenzyl Glycosides of Stemona tuberosa Roots[J]. J. Nat. Prod.2006,69(4):679-681
[38]Christian Zidorn,Ulrike Lohwasser, Susanne Pschorr, et al. Bibenzyls and dihydroisocoumarins from white salsify[J]. Phytochemistry,2005,66 (5):1691-1697
[39]Daniela M. Biondi, Concetta Rocco, Giuseppe Ruberto. Dihydrostilbene Derivatives from Glycyrrhiza glabra Leaves Daniela[J]. J. Nat. Prod.2005, 68(7):1099-1102
[40]Li Bai, Noriko Masukawa, Masae Yamaki, et al. Two Bibenzyl Glucosides From Pleione Bulbocodioides[J]. Phytochemistry,1997,44(8):1565-1567
[41]Zidorn C, Spitaler R, Ellmerer-Muller EP, et al. Structure of tyrolobibenzyl D and biological activity of tyrolobibenzyls from Scorzonera humilis[J]. Z Naturforsch C. 2002,57(7-8):614-9.
[42]Nagashima F, Kuba Y, Asakawa Y. Diterpenoids and aromatic compounds from the three New Zealand liverworts Jamesoniella kirkii, Balantiopsis rosea, and Radula species[J]. Chem Pharm Bull (Tokyo).2006,54(6):902-6.
[43]J. Heinrichs, H. Anton, S. R. Gradstein, et al. Surface wax, a new taxonomic feature in Plagiochilaceae[J]. Plant Syst. Evol.2000,225:225-233
[44]Pei-Lin Wu,Yu-Lin Hsu, Chen-Wei Zao, et al. Constituents of Vittaria anguste-elongata and Their Biological Activities[J]. J. Nat. Prod.2005,68(8): 1180-1184
[45]Zheng GQ, Ho DK, Elder PJ, et al. Ohioensins and pallidisetins:novel cytotoxic agents from the moss Polytrichum pallidisetum[J]. J Nat Prod.1994,57(1):32-41.
[46]Toyota M, Shimamura T, Ishii H, et al. New bibenzyl cannabinoid from the New Zealand liverwort Radula marginata[J]. Chem Pharm Bull (Tokyo). 2002,50(10):1390-2.
[47]Masao Toyota, Tomohide Kinugawa, Yoshinoiu Asakawa. Bibenzyl cannabinoid and bisbibenzyl derivative from the liverwort Radula perrottetii[J]. Phytochemistry,1994,37(3):859-862
[48]Taira Z, Takei M, Endo K,et al. Marchantin A trimethyl ether:its molecular structure and tubocurarine-like skeletal muscle relaxation activity[J]. Chem Pharm Bull (Tokyo).1994,42(1):52-6.
[49]Yoshinori Asakawa,Motoo Tori,Toru Masuya,et al. Ent-sesquiterpenoids and cyclic bis(bibenzyls) from the german liverwort Marchantia Polymorpha[J]. Phytochemistry.1990,29(5):1577-1584
[50]Han-Chao Wei,Shih-Jen Ma,Chia-LiWu.Sesquiterpenoids and cyclic bisbibenzyls from the liverwort reboulia hemisphaerica[J]. Phytochemistry,1995,39(1):91-97
[51]Motoo T., Mamiko A., Yoshinori A. Chenopodene, marchantin P and riccardin G from the liverwort Marchantia chenopoda[J]. Phtochemistry,1994,36:73-76
[52]Fumihiro Nagashima, Hiromi Izumo, Shigeru Takaoka, et al. Sesqui- and diterpenoids from the Panamanian liverwort Bryopteris filicina[J]. Phytochemistry,1994,37(2):433-439
[53]So ML,Chan WH,Xia PF,Cui Y. Two new cyclic bis(bibenzyl)s, isoriccardinquinone A and B from the liverwort Marchantia paleacea[J].Nat Prod Lett. 2002,16(3):167-71.
[54]Liu N, Guo DX, Wang YY, Wang LN, Ji M, Lou HX. Aromatic compounds from the liverwort Conocephalum japonicum[J]. Nat Prod Commun.2011,6(1):49-52.
[55]Fumihiro Nagashima, Shiori Momosaki, Yuko Watanabe, et al. Terpenoids and aromatic compounds from six liverworts[J]. Phytochemisrry,1996,41(1):207-211.
[56]Lu ZQ, Fan PH, Ji M, Lou HX. Terpenoids and bisbibenzyls from Chinese liverworts Conocephalum conicum and Dumortiera hirsute[J]. J Asian Nat Prod Res. 2006,8(1-2):187-92.
[57]Yoshida,T., Hashimoto,T., Takaoka,S.. et al. Phenolic constituents of the liverwort:Four novel cyclic bisbibenzyl dimers from Blasia pusilla L[J]. Tetrahedron,1996,52[46],14487-14500.
[58]Masao Toyota, Fumihiro Nagashima, Yoshinori Asakawa. Fatty acids and cyclic bis(bibenzyls) from the New Zealand liverwort Monoclea forsteri[J]. Phytochemistry,1988,27(8):2603-2608
[59]Xie CF, Qu JB, Wu XZ, Liu N, Ji M, Lou HX. Antifungal macrocyclic bis(bibenzyls) from the Chinese liverwort Ptagiochasm intermedlum L[J].Nat Prod Res.2010,24(6):515-20.
[60]Tori M., Aoki M., Asakawa Y..Chenopodene, marchantin P and riccardin G from the liverwort Marchantia chenopodaOriginal [J].Phytochemistry.1994,36(1):73-76.
[61]Niu C, Qu JB, Lou HX.Antifungal bis[bibenzyls] from the Chinese liverwort Marchantia polymorpha L. Chem Biodivers.2006,3(1):34-40.
[62]Wang LN, Xie CF, Zhu XS, Fan PH, Lou HX.Determination of atropisomeric configurations of macrocyclic bisbibenzyls by HPLC-CD/UV and quantum chemical calculations. J Asian Nat Prod Res.2011,13(4):312-8.
[63]Liu N, Guo DX, Wang YY, Wang LN, Ji M, Lou HX. Aromatic compounds from the liverwort Conocephalum japonicum.Nat Prod Commun.2011,6(1):49-52.
[64]Xie CF, Qu JB, Wu XZ, Liu N, Ji M, Lou HX.Antifungal macrocyclic bis(bibenzyls) from the Chinese liverwort Ptagiochasm intermedlum L. Nat Prod Res. 2010,24(6):515-20
[65]Morita H, Tomizawa Y, Tsuchiya T, Hirasawa Y, Hashimoto T, Asakawa Y.Antimitotic activity of two macrocyclic bis(bibenzyls), isoplagiochins A and B from the Liverwort Plagiochila fruticosa. Bioorg Med Chem Lett. 2009,15;19(2):493-6.
[66]Shy HS, Wu CL.Eudesmane-type sesquiterpenoids from the liverwort Lepidoziafauriana. J Asian Nat Prod Res.2006,8(8):723-31.
[67]Scher JM, Speakman JB, Zapp J, Becker H.Bioactivity guided isolation of antifungal compounds from the liverwort Bazzania trilobata (L.) S.F. Gray. Phytochemistry.2004,65(18):2583-8.
[68]Scher JM, Zapp J, Schmidt A, Becker H. Bazzanins L-R, chlorinated macrocyclic bisbibenzyls from the liverwort Lepidozia incurvata. Phytochemistry. 2003,64(3):791-6.
[69]Gibbons,S..Anti-staphylococcal Plant natural Products.Nat.Prod.Res.2004,21(2): 263-277.
[70]R.N.,Bhatla,S.C.(Eds.),Bryophyte Development:Physiology and Biochemistry. CRC Press, Boca Raton, pp.259-287.
[71]Guo, X.L., Leng, P., Yeng, Y., Yu, L.G., Lou, H. Plagiochin E, a botanic-derived phenolic compound, reverses fungal resistance to fluconazole relating to the efflux pump[J]. J. Appl. Microbiol.,2008.104(3):831-838.
[72]Wu, X.-Z., Cheng, A.-X., Sun, L.-M., Lou, H.-X. Effect of plagiochin E, an antifungal macrocyclic bis(bibenzyl), on cell wall chitin synthesis in Candida albicans[J]. Acta Pharmacol. Sin.2008,29(12):1478-1485.
[73]Wu, X.-Z., Cheng, A.X., Sun, L.-M., Sun, S.-J., Lou, H.-X.. Plagiochin E, an antifungal bis(bibenzyl), exerts its antifungal activity through mitochondrial dysfunction-induced reactive oxygen species accumulation in Candida albicans[J].Biochim. Biophys. Acta.2009,1790(8):770-777.
[74]Scher, J.M., Burgess, E.J., Lorimer, S.D., Perry, N.B.. A cytotoxic sesquiterpene and unprecedented sesquiterpene-bisbibenzyl compounds from the liverwort Schistochila glaucescens[J]. Tetrahedron 2002,58(38):7875-7882.
[75]Niu, C., Qu, J.-B., Lou, H.-X.. Antifungal bis(bibenzyls) from the Chinese liverwort Marchantia polymorpha[J]. Chem. Biodivers.2006,3(1):34-40.
[76]Scher, J.M., Speakman, J.-B., Zapp, J., Becker, H.. Bioactivity guided isolation of antifungal compounds from the liverwort Bazzania trilobata (L.) S.F. Gray[J]. Phytochemistry 2004,66(21),2583-2588
[77]Asakawa, Y., Toyota, M., Nagashima, F., Hashimoto, T.. Chemical constituents of selected Japanese and New Zealand liverworts[J]. Nat. Prod. Commun.2008,3, 289-300.
[78]Asakawa, Y., Ludwiczuk, A., Nagashima, F., et al. Bryophytes:bio- and chemical diversity, bioactivity and chemosystematics[J]. Heterocycles,2009,77,99-150.
[79]Iwai, Y.,Murakami, K., Gomi, Y.,et al. Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts[J]. PLoS ONE 2011,6(5):e19825.
[80]Asakawa, Y. Terpenoids and Aromatic Compounds with Pharmacological Activity from Bryophytes. In:Zinsmeister, D.H., Mues, R. (Eds.), Bryophytes:Their Chemistry and Chemical Taxonomy. Oxford University Press, Oxford, pp.369-410.
[81]Schwartner, C., Bor, W., Michel, C., et al. Effect of marchantins and related compounds on 5-lipoxygenase and cyclooxygenase and their antioxidant properties:a structure activity relationship study[J]. Phytomedicine,1995 2(2):113-117.
[82]Asakawa,Y., Toyota, M., Tori, M., Hashimoto, T. Chemical structures of macrocyclic bis(bibenzyls) isolated from liverworts(Hepaticae)[J]. Spectroscopy 2000,14:149-175
[83]Harinantenaina, L., Quang, D.N., Nishizawa, T., et al. Bioactive compounds from liverworts:inhibition of lipopolysaccharide-induced inducible NOS mRNA in RAW 264.7 cells by herbertenoids and cuparenoids[J]. Phytomedicine,2007 14(7-8): 486-491.
[84]Katsunuma, N. Molecular mechanisms of bone collagen degradation in bone resorption[J]. J. Bone Miner. Metab.1997,15:1-8.
[85]Matsunaga, Y., Saibara, T., Kido, H., Katsunuma, N..Participation of cathepsin B in processing of antigen presentation to MHC class Ⅱ[J]. FEBS Lett.1993, 324(3):325-330.
[86]Asakawa, Y. a. Liverworts-potential source of medicinal compounds [J]. Curr. Pharm. Design 2008,14(29),:3067-3088.
[87]Huang, WJ., Wu, CL., Lin, CW., et al. Marchantin A, a cyclic bis(bibenzyl ether), isolated from the liverwort Marchantia emarginata subsp. tosana induces apoptosis in human MCF-7 breast cancer cells[J]. Cancer Lett.2010,291(1):108-119.
[88]Schwartner, C., Michel, C., Stettmaier, K., Wagner, H., Bors, W. Marchantins and related polyphenols from liverwort:Physicochemical studies of their radical-scavenging properties[J]. Free Radical Biol. Med.1996,20(2):237-244.
[89]Hsiao, G., Teng, C.-M., Wu, C.-L., Ko, F.-N.. Marchantin H as a natural antioxidant and free radical scavenger[J]. Arch. Biochem. Biophys.1996,334(1): 18-26.
[90]Ko,F.N., Liao,C.H., Wu,C.L. Marchantinquinone, isolated from Reboulia hemisphaerica, as inhibitor of lipid peroxidation and as free radical scavenger[J]. Chem. Biol. Interact.1995,98(2):131-143
[91]Taira, Z., Takei, M., Endo, K., et al.. Marchantin A trimethyl ether:Its molecular structure and tubocurarine-like skeletal muscle relaxation activity[J]. Chem. Pharm. Bull.1994,42(1):52-56.
[92]Asakawa, Y.. Biologically Active Terpenoids and Aromatic Compounds from Liverworts and Inedible Mushroom Cryptoporus volvatus. In:Colegate, S.M., Molyneux, R.J. (Eds.), Bioactive Natural Products:Detection, Isolation, and Structural Determination. CRC Press, Boca Raton, pp.319-347.
[93]Tamehiro, N., Sato, Y., Suzuki, T.,et al. Riccardin C:a natural product that functions as a liver X receptor (LXR)a agonist and an LXRb antagonist[J]. FEBS Lett. 2005,579(24):5299-5304.
[94]Wei, H.C., Ma, S.J., Wu, C.L. Sesquiterpenoids and cyclic bisbibenzyls from the liverwort Reboulia hemisphaerica[J]. Phytochemistry,1995,39(1):91-97.
[95]Nagashima, F., Momosaki, S., Watanabe, Y., et al. Terpenoids and aromatic compounds from sixx liverworts[J]. Phytochemistry,1996,41(1):207-211.
[96]Suzuki, T., Tamehiro, N., Sato, Y., et al., The novel compounds that activate farnesoid X receptor:The diversity of their effects on gene expression[J]. J. Pharmacol. Sci.2008,107(3):285-294.
[97]Harinantenaina, L., Luang, D.N., Nishizawa, T., et al. Bis(bibenzyls) from liverworts inhibit lipopolysaccharideinduced inducible NOS in RAW 264.7 cells:A Study of structure-activity relationships and molecular mechanism[J]. J. Nat. Prod. 2005,68(12):1779-1781.
[98]Shi, Y.-Q., Liao, Y.-X., Qu, X.-J., et al. Marchantin C, a macrocyclic bisbibenzyl, induces apoptosis of human glioma A172 cells[J]. Cancer Lett.2008, 262(2):173-182.
[99]Shi, Y.-Q., Zhu, C.-J., Yuan, H.-Q., et al. Marchantin C, a novel microtubule inhibitor from liverwort with anti-tumor activity both in vivo and in vitro[J]. Cancer Lett.2009,276(2):160-170.
[100]Morita, H., Tomizawa, Y., Tsuchiya, T., et al. Antimitotic activity of two macrocyclic bis(bibenzyls), isoplagiochins A and B from the liverwort Plagiochila fruticosa. Bioorg[J]. Med. Chem. Lett.2009.19(2):493-496.
[101]Li, X., Sun, B., Zhu, C.J., et al. Reversal of P-glycoprotein-mediated multldrugresistance by maeroeyclic bisbibenzyl derivatives in adriamycin-ristant human myelogenousleukemia(K562/A02)cells[J]. Toxicology inVitro.2009,23(1):29.
[102]Scher,J., Burgess,E.J., Lorimerb,S.D., Perry,N.B. A cytotoxic sesquiterpene and unprecedented sesquiterpene-bisbibenzyl compounds from the liverwort Schistochila glaucescens[J]. Tetrahedron 2002,58(39):7875-7872
[103]Yoshida,T., Hashimoto,T., Takaoka,S., et al. Phenolic constituents of the liverwort:four novel cyclic bisbibenzyl dimmers from Blasia pusilla L[J]. Tetrahedron 1996,52(46):14487-14500.
[104]Dewick, P.M. Medicinal natural products:a biosynthetic approach (second ed.),John wiley&Sons Ltd., West Sussex,2002,P.28-29
[105]Ishida, A.; Ono, K.; Matsusaka, T., Cell wall-associated peroxidase in cultured cells of liverwort, Marchantia polymorpha L. Changes of peroxidase level and its localization in the cell wall[J]. Plant Cell Reports,1985,4(2):54-57.
[106]Zinsmeister H.D., BeekerH. Eieher. T. Bryophytes,a source of biologically active, naturally occurring material[J]. Angew Chem.Int.Ed.Engl.1991,30(2):130-147
[107]Friederich, S., Maier U.H., Deus-Neumann,B.,et al. Biosynthesis of cyclic bis (bibenzyls) in Marchantia polymorpha[J]. Phytochemistry,1999,50(4):589-598.
[108]Speicher,A., Heisel,R., Kolz, J.First detection of a chloroperoxidase in bryophytes[J]. Phytochemistry,2003,62(5):679-682.
[109]David,C.H., Timothy,W., Pcter,D. Howes Total Synthesis of Caviculannand and riccardinC:Addressing the Synthesis of an Arene That Adopts a Boat Configuration[J]. Angew. Chem.Int.Ed.2005,44(29):4499
[110]Fanta,P.E. The Ullmann Synthesis of Biaryls[J].Chem. Rev.,1946,38:139-96.
[111]Suzuki,A. Synthetic studies via the cross-coupling reaction of organoboron derivatives with organic halides[J]. Pure Appl.Chem.l991,63:419.
[112]Mlyaura,N., Suzuki,A. Palladium-Catalyzed Cross-C oupling Reactions of Organoboron Compounds[J]. Chem.Rev.1995,95(7):2457.
[113]David C. Harrowven, Sarah L. Kostiuk. Macrocylic bisbibenzyl natural products and their chemical synthesis[J]. Nat. Prod. Rep.,2012,29(2):223-242
[114]Mitsuaki Kodama, Yoshinori Shiobara, Hisako Sumitomo, et al. Total Syntheses of Marchantin A and Riccardin B, Cytotoxic Bis(bibenzyls) from Liverworts[J]. J. Org. Chem.1988,53(1),72-77
[115]Gottsegen, A., Nogradi, M., Vermes, B., et al.Total syntheses of riccardins A, B, and C, cytotoxic macrocyclic bis(bibenzyls) from Liverworts[J]. J. Chem. Soc. Perkin Trans.1990,1(2):315-320.
[116]Speicher,A., Groh, M., Zapp, J., et al. A Synthesis-Driven Structure Revision of 'Plagiochin E, a Highly Bioactive Bisbibenzyl[J]. Syn. lett.,2009,11:1852-1858.
[117]Speicher, A., Holz, J. Synthesis of marchantin C, a novel microtubule inhibitor from liverworts[J]. Tetrahedron Lett.2010,51(22):2986-2989.
[118]Esumi, T., Wada, M., Mizushima, E., et al. Efficient synthesis of isoplagiochin D, a macrocyclic bis(bibenzyls), by utilizing an intramolecular Suzuki-Miyaura reaction[J]. Tetrahedron Lett.,2004,45(37):6941-6945.
[119]Speicher,A., Backes, T., Hesidens,K., Kolz,J.. Ring strain and total syntheses of modified macrocycles of the isoplagiochin type[J]. Beilstein journal of organic chemistry,2009,1(5):71.
[120]Hioki, H., Shima, N., Kawaguchi. K., et al. Synthesis of riccardin C and its seven analogues. Part 1:The role of their phenolic hydroxyl groups as LXR [alpha] agonists[J]. Bioorganic & medicinal chemistry letters,2009,19(3):738-741.
[121]Sun,B., Yuan, H., Xi, G, Ma, Y.,Lou, H., Synthesis and multidrug resistance reversal activity of dihydroptychantol A and its novel derivatives [J]. Bioorganic & medicinal chemistr,2009,17(14):4981-4989.
[122]Jiang, J., Sun, B., Wang Y.Y., Cui M., Zhang L., Cui C.Z., Wang Y.F., Liu X.G., Lou H.X.. Synthesis of macrocyclic bisbibenzyl derivatives and their anticancer effects as anti-tubulin agents. Bioorganic & Medicinal Chemistry. 2012;20(7):2382-2391
[123]Xue, X., Qu, X. J., Gao, Z.H., Sun C.C., Liu H.P., Zhao C.R., Cheng Y.N., Lou H.X.. Riccardin D, a novel macrocyclic bisbibenzyl, induces apoptosis of human leukemia cells by targeting. DNA topoisomerase Ⅱ. Invest New Drugs 2012;30(1):212-222
[124]Sun, C.C., Zhang, Y.S., Xue, X., Cheng Y.N., Liu H.P., Zhao C.R., Lou H.X., Qu X.J.. Inhibition of angiogenesis involves in anticancer activity of riccardin D, a macrocyclic bisbibenzyl, in human lung carcinoma. European Journal of Pharmacology.2011;667(1-3):136-143.
[125]Xue, X., Sun, D.F., Sun, C.C., Liu H.P., Yue B, Zhao C.R., Lou H.X., Qu X.J.. Inhibitory effect of riccardin D on growth of human non-small cell lung cancer In vitro and in vivo studies. Lung Cancer.2012; 76(3):300-308.
[1]G. N. Bollenback, John W. Long, D. G. Benjamin, J. A. Lindquist. The Synthesis of Aryl-D-glucopyranosiduronic Acids[J].J. Am. Chem. Soc.,1955,77(12):3310-15.
[2]Seymour Bernstein, R. B. Conrow. Steroid conjugates. Ⅵ. Improved Koenigs--Knorr synthesis of aryl glucuronides using cadmium carbonate, a new and effective catalyst[J]. The Journal of Organic Chemistry,1971,36(7):863-870.
[3]W.D.S.Bowering,T.E.Timell. Synthesis and Characterization of 2-O-(β-D-Glucopyranosyluronic Acid)-D-xylopyranose[J]. J. Am. Chem. Soc.,1960,82(11):8287-8230.
[4]Henriette Kold Uldam, Martin Juhl, Henrik Pedersen, Lars Dalgaard. Biosynthesis and Identification of an N-Oxide/N-Glucuronide Metabolite and First Synthesis of an N-O-Glucuronide Metabolite of Lu AA21004[J]. Drug Metabolism and Disposition,2011,39(12):2264-2274.
[1]化学药物临床药代动力学技术指导原则.2005年3月.
[2]B.K.Matuszewski, M.L.Constanzer and C.M.Chavez-Eng. Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS[J]. Anal. Chem.,2003,75:3019-3030.
[1]Bringmann G., Muehlbacher J., Reichert M. Stereochemistry of isoplagiochin C a macrocyclic bisbibenzyl from liverworts[J]. J Am Chem Soc,2004,126(30):9283-9290
[2]Wang Li-ning, Xie Chun-feng, Lou Hong-xiang. Determination of atropisomeric configurations of macrocyclic bisbenzyls by HPLC-CD/UV and quantum chemical calculations[J]. J Asian Nat Prod Res.2011,13 (4):312-318
[3]吕蓓蓓色谱_质谱联用筛选苔藓植物中化学成分及片叶苔素D药代动力学分析
[4]Liu G, Zhang D, Jiao Y, Zheng D, Liu Y, Duan C, Jia L, Zhang Q, Lou H. Comparison of different methods for preparation of a stable riccardin D formulation via nano-technology. Int J Pharm.2012 Jan 17;422(1-2):516-22.
[1]朱大岭,韩维娜，张荣.细胞色素P450酶系在药物代谢中的作用[J].医药导报,2004,23(7)：4402443.
[2]Ioannides C,Lewis DF. Cytochromes P450 in the bioctivation of chemicals[J]. Curr Top Med Chem.2004,4 (16):1762-178.
[3]宣贵达,朱心强,郑一凡,等.大鼠肝细胞色素P4503A的性别差异[J].癌变·畸变·突变,1997,9(1)：50252.
[4]董海涛,吴健敏,余应年.细胞色素P4501A1基因mRNA的化学诱导及在人肝中的基础表达[J].中国药理学与毒理学杂志,1996,10(4)：2772280.
[5]汪保国,陈思东,陈阳,等.细胞色素P2E1和1A1多态性与肺癌关系的病理对照研究[J].肿瘤防治杂志,2004,11(7)：6812685.
[6]许振华,周宏灏.细胞色素氧化酶P450A2与药物代谢[J].中国临床药理学杂志,1996,12(2)：1152121.
[7]杨进波,蒋长征,柯磊,等.苯并芘诱导细胞色素P4501A1表达的研究[J].中华劳动卫生职业病杂志,2003,21(5)：3622364.
[8]王军升,许振华,周宏灏.细胞色素P4503A4与药物氧化代谢[J].中国临床药理学杂志,1996,12(2)：2312235.
[9]Jurgen Brockoller, MD, Julia Kircbbeiner, MD, Jurgen Schmider, MD, et al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and in the outcome of haloperidol treatment [J].Clin Pharmacol Ther,2002,72 (4):4382452.
[10]Henrike Wuttke,MD,Thomas Rau,MD,Roland Heide,BS,et al. Increased freqeuncy of cytochrome P450 2D6 poor metabolizers among patiens with metoprolol2associzationadverse effects [J].Clinical Pharmacology & Therapeutics.2002,72 (4):4302437.
[11]Julia Kircbbeiner, MD, Jurgen BrockmE ller, MD, Ingolf Meineke, PhD, et al. Impact of the CYP2C9 amino acid polymorphisms on glyburide kinetics andon the insulin and glucose response in heathy volunteers [J]. Clin Pharmacol. Ther.2002,72 (4):2862295.
[12]李德淳,朱理璎.药物代谢酶昼夜节律的变化观察与中医学“择时用药”原则探讨[J].中草药,1996,27(8)：4792481.
[13]Lin JH, Lu AYH. Inhibition and Induction of Cytochrome P450 and the Clinical Implications[J]. Clinical Pharmacokinetics,1998,35 (5):3612390.
[14]《药物开发过程中药物代谢／药物相互作用研究(体外研究)》指南
[1]《化学药物杂质研究的技术指导原则》,2005年3月
[2]《化学药物质量控制分析方法验证技术指导原则》,2009年
[3]《化学药物残留溶剂研究的技术指导原则》,2009年
[41《中国药典》2010年版二部,2009年
[2]衣艳君,中国药用苔藓植物资源[J].中草药,2000,31(08)：624-628.
[3]Asakawa Y, Ludwiczuk A, Nagashima F. Phytochemical and biological studies of bryophytes[J]. Phytochemistry.2012 May 29(In press).
[4]Asakawa. Y.. Chemosystematics of the Hepaticae[J]. Phytochemistry,2004, 65(6):623-669.
[5]Asakawa, Y.. Biologically active compounds from bryophytes[J]. Pure and Applied Chemistry,2007,79,557-580.
[6]Harinantenaina,L.,Quang,D.N., Takeshi,N., Hashimoto,T.,Kohchi,C.:Soma, J.I., Asakawa,Y. Bis(bibenzyls) from liverworts inhibit lipopolysaccharide-induced inducible NOS in RAW 264.7 cells:a study of structure-activity relationships and molecular mechanism[J].J Nat. Prod.,2005,68(12):1779-81
[7]Seung-Hwa Baek, Richard K. Phipps,Nigel B. Perry. Antimicrobial Chlorinated Bibenzyls from the Liverwort Riccardia marginata[J]. J. Nat. Prod.2004, 67(4):718-720
[8]Labbe C, Faini F, Villagran C, Coll J, Rycroft DS. Bioactive polychlorinated bibenzyls from the liverwort Riccardia polyclada[J]. J Nat Prod.2007,70(12):2019-21.
[9]Asakawa, Y. Chemical constituents of the Bryophytes. In W. Herz, E. W. Kirby, R. E. Moore, W. Steglich, & Ch. Tamm, Progress in the Chemistry of Organic Natural Products,1995,65,1-618
[10]Hermann Anton, Ralph Schoeneborn, Ruediger Mues. Bibenzyls and bisbibenzyls from a neotropical Plagiochila species[J]. Phytochemistry 1999,52(8):1639-1645
[11]Dadid S.,W. John Cole, Nadia Aslam. Bibenzyls and bisbibenzyls from a neotropical Plagiochila species[J]. Phytochemistry,1998,49(1):145-148
[12]Stephan H.,Wilfried A.,Konig. A.2-arylbenzofurans of presumed stilbenoid origin from Corsinia coriandrina (Hepaticae)[J]. Phytochemistry,2004,23(65):3113-3118
[13]Hermann Anton,Ludwig Kraut, Rijdiger Muest, Mariai Morales Z. Phenznthrenes and Bibenzyls From a Plagiochila Species[J].Phytochemistry,1997,46(6):1069-1075
[14]Frank Cullamnn, Hans Becker,Enriqlje Pandolfi, et al. Bibenzyl Derivatives From PELLIA EPIPHYLLA[J].Phytochemistry,1997,45(6):1235-1247
[15]Joseph D.Connollya,David S.Rycrofta,Dharmatma L., et al. Aromatic compounds from the liverwort Plagiochila spinulos[J]. Phytochemistry,1999,50(7):1159-1165
[16]Pei-Lin Wu,Yu-Lin Hsu, Chen-Wei Zao, et al.Constituents of Vittaria anguste-elongata and Their Biological Activities[J]. J. Nat. Prod.2005,68(8): 1180-1184
[17]Alicia Bardona, Graciela Bovi Mitrea, Norma Kamiyaa, et al. Eremophilanolides and other constituents from the Argentine liverwort Frullania brasiliensis[J].Phytochemistry,2002,59(2),205-213
[18]Ronlan, A., Hammerich, O., Parker, V.D.. Anodic oxidation of methoxybibenzyls. Products and mechanism of the intramolecular cyclization[J]. Journal of the American Chemical Society,1973,95:7132-7138.
[19]Siegmund Kunz, Hans Becker. Bibenzyl derivatives from the liverwort Ricciocarpos natans[J].Phytochemistry,1994,36(3),675-677
[20]Zhang,G.N., Zhang,C.F., Wang,Z.T., Xu,L.S.. Studies on Chemical Constituents of Dendrobium thyrsiflorum Rchb.f [J]Chin. J. Nat. Med.,2004,2:78
[21]Hermann Anton,Ludwig Kraut, Rijdiger Muest, Mariai Morales Z. Phenznthrenes and Bibenzyls From a Plagiochila Species[J].Phytochemistry,1997,46(6):1069-1075
[22]Lou HX, Li GY,Wang FQ.A cytotoxic diterpenoid and antifungal phenolic compounds from Frullania muscicola Steph[J]. J Asian Nat Prod Res.2002,4(2): 87-94.
[23]Yoshida,T., Hashimoto,T., Takaoka,S., et al. Phenolic constituents of the liverwort:Four novel cyclic bisbibenzyl dimers from Blasia pusilla LOriginal Research Article[J].Tetrahedron,1996,52(46):14487.
[24]Nagashima F, Toyota M, Asakawa Y. Bazzanane sesquiterpenoids from the New Zealand liverwort Frullania falciloba[J]. Chem Pharm Bull.2006;54(9):1347-9.
[25]Ludwig Kraut, Riidiger Mues, Hans Dietmar Zinsmeister. Prenylated bibenzyl derivatives from Lethocolea glossophylla and Radula volute[J]. Phytochemistry,1997,45(6) 1249-1255
[26]Daniela M. Biondi, Concetta Rocco, Giuseppe Ruberto. New Dihydrostilbene Derivatives from the Leaves of Glycyrrhiza glabra and Evaluation of Their Antioxidant Activity[J]. J. Nat. Prod.2003,66(4):477-480
[27]Samneang Apisantiyakom, Prasat Kittakoop, Thanaporn Manyuma, et al. Novel Biologically Active Bibenzyls from Bauhinia saccocalyx PIERRE[J]. Chem. Biodiv.,2004,1(11):1694
[28]Biondi,D.M., Roeeo,C., Ruberto,G.J. Dihydrostilbene derivatives from Glycyrrhiza glabra leaves[J].Nat.Prod.,2005,68(7):1099-102
[29]Hermann Anton, Ludwig Kraut, Rijdiger Muest, et al.Z. Phenznthrenes and Bibenzyls From a Plagiochila Species[J].Phytochemistry,1997,46(6):1069-1075
[30]Masao Toyota, Tomohide Kinugawa, Yoshinoiu Asakawa. Bibenzyl cannabinoid and bisbibenzyl derivative from the liverwort Radula perrottetii[J]. Bibenzyl cannabinoid and bisbibenzyl derivative from the liverwort Radula perrottetii[J]. Phytochemistry,1994,37(3):859-862
[31]Masao Toyota, Eri Nakaishi, Yoshinori Asakaw. Eudesmane-type sesquiterpenoids from the liverwort Lepidozia vitreaOrigina[J]. Photochemistry, 1996,41(3):833-836.
[32]Nagashima F, Kuba Y, Asakawa Y. Diterpenoids and aromatic compounds from the three New Zealand liverworts Jamesoniella kirkii, Balantiopsis rosea, and Radula species[J]. Chem Pharm Bull (Tokyo).2006 Jun;54(6):902-6.
[33]Qu JB, Xie CF, Ji M, et al. Water-soluble constituents from the Liverwort Marchantia polymorpha [J]. Helv Chim Acta,2007,90:2109-2115.
[34]Siegmund Kunz, Hans Becker Bibenzyl glycosides from the liverwort Ricciocarpos natans[J].Phytochemistry,1992,31(11):3981-3983
[35]Sianne Schwikkard, Bing-Nan Zhou, Thomas E. Glass, et al. Bioactive Compounds from Combretum erythrophyllum[J].J. Nat. Prod.2000,63(4):457-460
[36]HAN Guang-Xuan, WANG Li-Xin, ZHANG Wei-Dong, et al. Studies on chemical constituents of Bletilla striata(Ⅱ)[J] Acad. J. Sec. Mil. Med. Univ.,2002,23(9):1029-1031
[37]Ki Yong Lee, Sang Hyun Sung, Young Choong Kim. Neuroprotective Bibenzyl Glycosides of Stemona tuberosa Roots[J]. J. Nat. Prod.2006,69(4):679-681
[38]Christian Zidorn,Ulrike Lohwasser, Susanne Pschorr, et al. Bibenzyls and dihydroisocoumarins from white salsify[J]. Phytochemistry,2005,66 (5):1691-1697
[39]Daniela M. Biondi, Concetta Rocco, Giuseppe Ruberto. Dihydrostilbene Derivatives from Glycyrrhiza glabra Leaves Daniela[J]. J. Nat. Prod.2005, 68(7):1099-1102
[40]Li Bai, Noriko Masukawa, Masae Yamaki, et al. Two Bibenzyl Glucosides From Pleione Bulbocodioides[J]. Phytochemistry,1997,44(8):1565-1567
[41]Zidorn C, Spitaler R, Ellmerer-Muller EP, et al. Structure of tyrolobibenzyl D and biological activity of tyrolobibenzyls from Scorzonera humilis[J]. Z Naturforsch C. 2002,57(7-8):614-9.
[42]Nagashima F, Kuba Y, Asakawa Y. Diterpenoids and aromatic compounds from the three New Zealand liverworts Jamesoniella kirkii, Balantiopsis rosea, and Radula species[J]. Chem Pharm Bull (Tokyo).2006,54(6):902-6.
[43]J. Heinrichs, H. Anton, S. R. Gradstein, et al. Surface wax, a new taxonomic feature in Plagiochilaceae[J]. Plant Syst. Evol.2000,225:225-233
[44]Pei-Lin Wu,Yu-Lin Hsu, Chen-Wei Zao, et al. Constituents of Vittaria anguste-elongata and Their Biological Activities[J]. J. Nat. Prod.2005,68(8): 1180-1184
[45]Zheng GQ, Ho DK, Elder PJ, et al. Ohioensins and pallidisetins:novel cytotoxic agents from the moss Polytrichum pallidisetum[J]. J Nat Prod.1994,57(1):32-41.
[46]Toyota M, Shimamura T, Ishii H, et al. New bibenzyl cannabinoid from the New Zealand liverwort Radula marginata[J]. Chem Pharm Bull (Tokyo). 2002,50(10):1390-2.
[47]Masao Toyota, Tomohide Kinugawa, Yoshinoiu Asakawa. Bibenzyl cannabinoid and bisbibenzyl derivative from the liverwort Radula perrottetii[J]. Phytochemistry,1994,37(3):859-862
[48]Taira Z, Takei M, Endo K,et al. Marchantin A trimethyl ether:its molecular structure and tubocurarine-like skeletal muscle relaxation activity[J]. Chem Pharm Bull (Tokyo).1994,42(1):52-6.
[49]Yoshinori Asakawa,Motoo Tori,Toru Masuya,et al. Ent-sesquiterpenoids and cyclic bis(bibenzyls) from the german liverwort Marchantia Polymorpha[J]. Phytochemistry.1990,29(5):1577-1584
[50]Han-Chao Wei,Shih-Jen Ma,Chia-LiWu.Sesquiterpenoids and cyclic bisbibenzyls from the liverwort reboulia hemisphaerica[J]. Phytochemistry,1995,39(1):91-97
[51]Motoo T., Mamiko A., Yoshinori A. Chenopodene, marchantin P and riccardin G from the liverwort Marchantia chenopoda[J]. Phtochemistry,1994,36:73-76
[52]Fumihiro Nagashima, Hiromi Izumo, Shigeru Takaoka, et al. Sesqui- and diterpenoids from the Panamanian liverwort Bryopteris filicina[J]. Phytochemistry,1994,37(2):433-439
[53]So ML,Chan WH,Xia PF,Cui Y. Two new cyclic bis(bibenzyl)s, isoriccardinquinone A and B from the liverwort Marchantia paleacea[J].Nat Prod Lett. 2002,16(3):167-71.
[54]Liu N, Guo DX, Wang YY, Wang LN, Ji M, Lou HX. Aromatic compounds from the liverwort Conocephalum japonicum[J]. Nat Prod Commun.2011,6(1):49-52.
[55]Fumihiro Nagashima, Shiori Momosaki, Yuko Watanabe, et al. Terpenoids and aromatic compounds from six liverworts[J]. Phytochemisrry,1996,41(1):207-211.
[56]Lu ZQ, Fan PH, Ji M, Lou HX. Terpenoids and bisbibenzyls from Chinese liverworts Conocephalum conicum and Dumortiera hirsute[J]. J Asian Nat Prod Res. 2006,8(1-2):187-92.
[57]Yoshida,T., Hashimoto,T., Takaoka,S.. et al. Phenolic constituents of the liverwort:Four novel cyclic bisbibenzyl dimers from Blasia pusilla L[J]. Tetrahedron,1996,52[46],14487-14500.
[58]Masao Toyota, Fumihiro Nagashima, Yoshinori Asakawa. Fatty acids and cyclic bis(bibenzyls) from the New Zealand liverwort Monoclea forsteri[J]. Phytochemistry,1988,27(8):2603-2608
[59]Xie CF, Qu JB, Wu XZ, Liu N, Ji M, Lou HX. Antifungal macrocyclic bis(bibenzyls) from the Chinese liverwort Ptagiochasm intermedlum L[J].Nat Prod Res.2010,24(6):515-20.
[60]Tori M., Aoki M., Asakawa Y..Chenopodene, marchantin P and riccardin G from the liverwort Marchantia chenopodaOriginal [J].Phytochemistry.1994,36(1):73-76.
[61]Niu C, Qu JB, Lou HX.Antifungal bis[bibenzyls] from the Chinese liverwort Marchantia polymorpha L. Chem Biodivers.2006,3(1):34-40.
[62]Wang LN, Xie CF, Zhu XS, Fan PH, Lou HX.Determination of atropisomeric configurations of macrocyclic bisbibenzyls by HPLC-CD/UV and quantum chemical calculations. J Asian Nat Prod Res.2011,13(4):312-8.
[63]Liu N, Guo DX, Wang YY, Wang LN, Ji M, Lou HX. Aromatic compounds from the liverwort Conocephalum japonicum.Nat Prod Commun.2011,6(1):49-52.
[64]Xie CF, Qu JB, Wu XZ, Liu N, Ji M, Lou HX.Antifungal macrocyclic bis(bibenzyls) from the Chinese liverwort Ptagiochasm intermedlum L. Nat Prod Res. 2010,24(6):515-20
[65]Morita H, Tomizawa Y, Tsuchiya T, Hirasawa Y, Hashimoto T, Asakawa Y.Antimitotic activity of two macrocyclic bis(bibenzyls), isoplagiochins A and B from the Liverwort Plagiochila fruticosa. Bioorg Med Chem Lett. 2009,15;19(2):493-6.
[66]Shy HS, Wu CL.Eudesmane-type sesquiterpenoids from the liverwort Lepidoziafauriana. J Asian Nat Prod Res.2006,8(8):723-31.
[67]Scher JM, Speakman JB, Zapp J, Becker H.Bioactivity guided isolation of antifungal compounds from the liverwort Bazzania trilobata (L.) S.F. Gray. Phytochemistry.2004,65(18):2583-8.
[68]Scher JM, Zapp J, Schmidt A, Becker H. Bazzanins L-R, chlorinated macrocyclic bisbibenzyls from the liverwort Lepidozia incurvata. Phytochemistry. 2003,64(3):791-6.
[69]Gibbons,S..Anti-staphylococcal Plant natural Products.Nat.Prod.Res.2004,21(2): 263-277.
[70]R.N.,Bhatla,S.C.(Eds.),Bryophyte Development:Physiology and Biochemistry. CRC Press, Boca Raton, pp.259-287.
[71]Guo, X.L., Leng, P., Yeng, Y., Yu, L.G., Lou, H. Plagiochin E, a botanic-derived phenolic compound, reverses fungal resistance to fluconazole relating to the efflux pump[J]. J. Appl. Microbiol.,2008.104(3):831-838.
[72]Wu, X.-Z., Cheng, A.-X., Sun, L.-M., Lou, H.-X. Effect of plagiochin E, an antifungal macrocyclic bis(bibenzyl), on cell wall chitin synthesis in Candida albicans[J]. Acta Pharmacol. Sin.2008,29(12):1478-1485.
[73]Wu, X.-Z., Cheng, A.X., Sun, L.-M., Sun, S.-J., Lou, H.-X.. Plagiochin E, an antifungal bis(bibenzyl), exerts its antifungal activity through mitochondrial dysfunction-induced reactive oxygen species accumulation in Candida albicans[J].Biochim. Biophys. Acta.2009,1790(8):770-777.
[74]Scher, J.M., Burgess, E.J., Lorimer, S.D., Perry, N.B.. A cytotoxic sesquiterpene and unprecedented sesquiterpene-bisbibenzyl compounds from the liverwort Schistochila glaucescens[J]. Tetrahedron 2002,58(38):7875-7882.
[75]Niu, C., Qu, J.-B., Lou, H.-X.. Antifungal bis(bibenzyls) from the Chinese liverwort Marchantia polymorpha[J]. Chem. Biodivers.2006,3(1):34-40.
[76]Scher, J.M., Speakman, J.-B., Zapp, J., Becker, H.. Bioactivity guided isolation of antifungal compounds from the liverwort Bazzania trilobata (L.) S.F. Gray[J]. Phytochemistry 2004,66(21),2583-2588
[77]Asakawa, Y., Toyota, M., Nagashima, F., Hashimoto, T.. Chemical constituents of selected Japanese and New Zealand liverworts[J]. Nat. Prod. Commun.2008,3, 289-300.
[78]Asakawa, Y., Ludwiczuk, A., Nagashima, F., et al. Bryophytes:bio- and chemical diversity, bioactivity and chemosystematics[J]. Heterocycles,2009,77,99-150.
[79]Iwai, Y.,Murakami, K., Gomi, Y.,et al. Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts[J]. PLoS ONE 2011,6(5):e19825.
[80]Asakawa, Y. Terpenoids and Aromatic Compounds with Pharmacological Activity from Bryophytes. In:Zinsmeister, D.H., Mues, R. (Eds.), Bryophytes:Their Chemistry and Chemical Taxonomy. Oxford University Press, Oxford, pp.369-410.
[81]Schwartner, C., Bor, W., Michel, C., et al. Effect of marchantins and related compounds on 5-lipoxygenase and cyclooxygenase and their antioxidant properties:a structure activity relationship study[J]. Phytomedicine,1995 2(2):113-117.
[82]Asakawa,Y., Toyota, M., Tori, M., Hashimoto, T. Chemical structures of macrocyclic bis(bibenzyls) isolated from liverworts(Hepaticae)[J]. Spectroscopy 2000,14:149-175
[83]Harinantenaina, L., Quang, D.N., Nishizawa, T., et al. Bioactive compounds from liverworts:inhibition of lipopolysaccharide-induced inducible NOS mRNA in RAW 264.7 cells by herbertenoids and cuparenoids[J]. Phytomedicine,2007 14(7-8): 486-491.
[84]Katsunuma, N. Molecular mechanisms of bone collagen degradation in bone resorption[J]. J. Bone Miner. Metab.1997,15:1-8.
[85]Matsunaga, Y., Saibara, T., Kido, H., Katsunuma, N..Participation of cathepsin B in processing of antigen presentation to MHC class Ⅱ[J]. FEBS Lett.1993, 324(3):325-330.
[86]Asakawa, Y. a. Liverworts-potential source of medicinal compounds [J]. Curr. Pharm. Design 2008,14(29),:3067-3088.
[87]Huang, WJ., Wu, CL., Lin, CW., et al. Marchantin A, a cyclic bis(bibenzyl ether), isolated from the liverwort Marchantia emarginata subsp. tosana induces apoptosis in human MCF-7 breast cancer cells[J]. Cancer Lett.2010,291(1):108-119.
[88]Schwartner, C., Michel, C., Stettmaier, K., Wagner, H., Bors, W. Marchantins and related polyphenols from liverwort:Physicochemical studies of their radical-scavenging properties[J]. Free Radical Biol. Med.1996,20(2):237-244.
[89]Hsiao, G., Teng, C.-M., Wu, C.-L., Ko, F.-N.. Marchantin H as a natural antioxidant and free radical scavenger[J]. Arch. Biochem. Biophys.1996,334(1): 18-26.
[90]Ko,F.N., Liao,C.H., Wu,C.L. Marchantinquinone, isolated from Reboulia hemisphaerica, as inhibitor of lipid peroxidation and as free radical scavenger[J]. Chem. Biol. Interact.1995,98(2):131-143
[91]Taira, Z., Takei, M., Endo, K., et al.. Marchantin A trimethyl ether:Its molecular structure and tubocurarine-like skeletal muscle relaxation activity[J]. Chem. Pharm. Bull.1994,42(1):52-56.
[92]Asakawa, Y.. Biologically Active Terpenoids and Aromatic Compounds from Liverworts and Inedible Mushroom Cryptoporus volvatus. In:Colegate, S.M., Molyneux, R.J. (Eds.), Bioactive Natural Products:Detection, Isolation, and Structural Determination. CRC Press, Boca Raton, pp.319-347.
[93]Tamehiro, N., Sato, Y., Suzuki, T.,et al. Riccardin C:a natural product that functions as a liver X receptor (LXR)a agonist and an LXRb antagonist[J]. FEBS Lett. 2005,579(24):5299-5304.
[94]Wei, H.C., Ma, S.J., Wu, C.L. Sesquiterpenoids and cyclic bisbibenzyls from the liverwort Reboulia hemisphaerica[J]. Phytochemistry,1995,39(1):91-97.
[95]Nagashima, F., Momosaki, S., Watanabe, Y., et al. Terpenoids and aromatic compounds from sixx liverworts[J]. Phytochemistry,1996,41(1):207-211.
[96]Suzuki, T., Tamehiro, N., Sato, Y., et al., The novel compounds that activate farnesoid X receptor:The diversity of their effects on gene expression[J]. J. Pharmacol. Sci.2008,107(3):285-294.
[97]Harinantenaina, L., Luang, D.N., Nishizawa, T., et al. Bis(bibenzyls) from liverworts inhibit lipopolysaccharideinduced inducible NOS in RAW 264.7 cells:A Study of structure-activity relationships and molecular mechanism[J]. J. Nat. Prod. 2005,68(12):1779-1781.
[98]Shi, Y.-Q., Liao, Y.-X., Qu, X.-J., et al. Marchantin C, a macrocyclic bisbibenzyl, induces apoptosis of human glioma A172 cells[J]. Cancer Lett.2008, 262(2):173-182.
[99]Shi, Y.-Q., Zhu, C.-J., Yuan, H.-Q., et al. Marchantin C, a novel microtubule inhibitor from liverwort with anti-tumor activity both in vivo and in vitro[J]. Cancer Lett.2009,276(2):160-170.
[100]Morita, H., Tomizawa, Y., Tsuchiya, T., et al. Antimitotic activity of two macrocyclic bis(bibenzyls), isoplagiochins A and B from the liverwort Plagiochila fruticosa. Bioorg[J]. Med. Chem. Lett.2009.19(2):493-496.
[101]Li, X., Sun, B., Zhu, C.J., et al. Reversal of P-glycoprotein-mediated multldrugresistance by maeroeyclic bisbibenzyl derivatives in adriamycin-ristant human myelogenousleukemia(K562/A02)cells[J]. Toxicology inVitro.2009,23(1):29.
[102]Scher,J., Burgess,E.J., Lorimerb,S.D., Perry,N.B. A cytotoxic sesquiterpene and unprecedented sesquiterpene-bisbibenzyl compounds from the liverwort Schistochila glaucescens[J]. Tetrahedron 2002,58(39):7875-7872
[103]Yoshida,T., Hashimoto,T., Takaoka,S., et al. Phenolic constituents of the liverwort:four novel cyclic bisbibenzyl dimmers from Blasia pusilla L[J]. Tetrahedron 1996,52(46):14487-14500.
[104]Dewick, P.M. Medicinal natural products:a biosynthetic approach (second ed.),John wiley&Sons Ltd., West Sussex,2002,P.28-29
[105]Ishida, A.; Ono, K.; Matsusaka, T., Cell wall-associated peroxidase in cultured cells of liverwort, Marchantia polymorpha L. Changes of peroxidase level and its localization in the cell wall[J]. Plant Cell Reports,1985,4(2):54-57.
[106]Zinsmeister H.D., BeekerH. Eieher. T. Bryophytes,a source of biologically active, naturally occurring material[J]. Angew Chem.Int.Ed.Engl.1991,30(2):130-147
[107]Friederich, S., Maier U.H., Deus-Neumann,B.,et al. Biosynthesis of cyclic bis (bibenzyls) in Marchantia polymorpha[J]. Phytochemistry,1999,50(4):589-598.
[108]Speicher,A., Heisel,R., Kolz, J.First detection of a chloroperoxidase in bryophytes[J]. Phytochemistry,2003,62(5):679-682.
[109]David,C.H., Timothy,W., Pcter,D. Howes Total Synthesis of Caviculannand and riccardinC:Addressing the Synthesis of an Arene That Adopts a Boat Configuration[J]. Angew. Chem.Int.Ed.2005,44(29):4499
[110]Fanta,P.E. The Ullmann Synthesis of Biaryls[J].Chem. Rev.,1946,38:139-96.
[111]Suzuki,A. Synthetic studies via the cross-coupling reaction of organoboron derivatives with organic halides[J]. Pure Appl.Chem.l991,63:419.
[112]Mlyaura,N., Suzuki,A. Palladium-Catalyzed Cross-C oupling Reactions of Organoboron Compounds[J]. Chem.Rev.1995,95(7):2457.
[113]David C. Harrowven, Sarah L. Kostiuk. Macrocylic bisbibenzyl natural products and their chemical synthesis[J]. Nat. Prod. Rep.,2012,29(2):223-242
[114]Mitsuaki Kodama, Yoshinori Shiobara, Hisako Sumitomo, et al. Total Syntheses of Marchantin A and Riccardin B, Cytotoxic Bis(bibenzyls) from Liverworts[J]. J. Org. Chem.1988,53(1),72-77
[115]Gottsegen, A., Nogradi, M., Vermes, B., et al.Total syntheses of riccardins A, B, and C, cytotoxic macrocyclic bis(bibenzyls) from Liverworts[J]. J. Chem. Soc. Perkin Trans.1990,1(2):315-320.
[116]Speicher,A., Groh, M., Zapp, J., et al. A Synthesis-Driven Structure Revision of 'Plagiochin E, a Highly Bioactive Bisbibenzyl[J]. Syn. lett.,2009,11:1852-1858.
[117]Speicher, A., Holz, J. Synthesis of marchantin C, a novel microtubule inhibitor from liverworts[J]. Tetrahedron Lett.2010,51(22):2986-2989.
[118]Esumi, T., Wada, M., Mizushima, E., et al. Efficient synthesis of isoplagiochin D, a macrocyclic bis(bibenzyls), by utilizing an intramolecular Suzuki-Miyaura reaction[J]. Tetrahedron Lett.,2004,45(37):6941-6945.
[119]Speicher,A., Backes, T., Hesidens,K., Kolz,J.. Ring strain and total syntheses of modified macrocycles of the isoplagiochin type[J]. Beilstein journal of organic chemistry,2009,1(5):71.
[120]Hioki, H., Shima, N., Kawaguchi. K., et al. Synthesis of riccardin C and its seven analogues. Part 1:The role of their phenolic hydroxyl groups as LXR [alpha] agonists[J]. Bioorganic & medicinal chemistry letters,2009,19(3):738-741.
[121]Sun,B., Yuan, H., Xi, G, Ma, Y.,Lou, H., Synthesis and multidrug resistance reversal activity of dihydroptychantol A and its novel derivatives [J]. Bioorganic & medicinal chemistr,2009,17(14):4981-4989.
[122]Jiang, J., Sun, B., Wang Y.Y., Cui M., Zhang L., Cui C.Z., Wang Y.F., Liu X.G., Lou H.X.. Synthesis of macrocyclic bisbibenzyl derivatives and their anticancer effects as anti-tubulin agents. Bioorganic & Medicinal Chemistry. 2012;20(7):2382-2391
[123]Xue, X., Qu, X. J., Gao, Z.H., Sun C.C., Liu H.P., Zhao C.R., Cheng Y.N., Lou H.X.. Riccardin D, a novel macrocyclic bisbibenzyl, induces apoptosis of human leukemia cells by targeting. DNA topoisomerase Ⅱ. Invest New Drugs 2012;30(1):212-222
[124]Sun, C.C., Zhang, Y.S., Xue, X., Cheng Y.N., Liu H.P., Zhao C.R., Lou H.X., Qu X.J.. Inhibition of angiogenesis involves in anticancer activity of riccardin D, a macrocyclic bisbibenzyl, in human lung carcinoma. European Journal of Pharmacology.2011;667(1-3):136-143.
[125]Xue, X., Sun, D.F., Sun, C.C., Liu H.P., Yue B, Zhao C.R., Lou H.X., Qu X.J.. Inhibitory effect of riccardin D on growth of human non-small cell lung cancer In vitro and in vivo studies. Lung Cancer.2012; 76(3):300-308.
[1]G. N. Bollenback, John W. Long, D. G. Benjamin, J. A. Lindquist. The Synthesis of Aryl-D-glucopyranosiduronic Acids[J].J. Am. Chem. Soc.,1955,77(12):3310-15.
[2]Seymour Bernstein, R. B. Conrow. Steroid conjugates. Ⅵ. Improved Koenigs--Knorr synthesis of aryl glucuronides using cadmium carbonate, a new and effective catalyst[J]. The Journal of Organic Chemistry,1971,36(7):863-870.
[3]W.D.S.Bowering,T.E.Timell. Synthesis and Characterization of 2-O-(β-D-Glucopyranosyluronic Acid)-D-xylopyranose[J]. J. Am. Chem. Soc.,1960,82(11):8287-8230.
[4]Henriette Kold Uldam, Martin Juhl, Henrik Pedersen, Lars Dalgaard. Biosynthesis and Identification of an N-Oxide/N-Glucuronide Metabolite and First Synthesis of an N-O-Glucuronide Metabolite of Lu AA21004[J]. Drug Metabolism and Disposition,2011,39(12):2264-2274.
[1]化学药物临床药代动力学技术指导原则.2005年3月.
[2]B.K.Matuszewski, M.L.Constanzer and C.M.Chavez-Eng. Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS[J]. Anal. Chem.,2003,75:3019-3030.
[1]Bringmann G., Muehlbacher J., Reichert M. Stereochemistry of isoplagiochin C a macrocyclic bisbibenzyl from liverworts[J]. J Am Chem Soc,2004,126(30):9283-9290
[2]Wang Li-ning, Xie Chun-feng, Lou Hong-xiang. Determination of atropisomeric configurations of macrocyclic bisbenzyls by HPLC-CD/UV and quantum chemical calculations[J]. J Asian Nat Prod Res.2011,13 (4):312-318
[3]吕蓓蓓色谱_质谱联用筛选苔藓植物中化学成分及片叶苔素D药代动力学分析
[4]Liu G, Zhang D, Jiao Y, Zheng D, Liu Y, Duan C, Jia L, Zhang Q, Lou H. Comparison of different methods for preparation of a stable riccardin D formulation via nano-technology. Int J Pharm.2012 Jan 17;422(1-2):516-22.
[1]朱大岭,韩维娜，张荣.细胞色素P450酶系在药物代谢中的作用[J].医药导报,2004,23(7)：4402443.
[2]Ioannides C,Lewis DF. Cytochromes P450 in the bioctivation of chemicals[J]. Curr Top Med Chem.2004,4 (16):1762-178.
[3]宣贵达,朱心强,郑一凡,等.大鼠肝细胞色素P4503A的性别差异[J].癌变·畸变·突变,1997,9(1)：50252.
[4]董海涛,吴健敏,余应年.细胞色素P4501A1基因mRNA的化学诱导及在人肝中的基础表达[J].中国药理学与毒理学杂志,1996,10(4)：2772280.
[5]汪保国,陈思东,陈阳,等.细胞色素P2E1和1A1多态性与肺癌关系的病理对照研究[J].肿瘤防治杂志,2004,11(7)：6812685.
[6]许振华,周宏灏.细胞色素氧化酶P450A2与药物代谢[J].中国临床药理学杂志,1996,12(2)：1152121.
[7]杨进波,蒋长征,柯磊,等.苯并芘诱导细胞色素P4501A1表达的研究[J].中华劳动卫生职业病杂志,2003,21(5)：3622364.
[8]王军升,许振华,周宏灏.细胞色素P4503A4与药物氧化代谢[J].中国临床药理学杂志,1996,12(2)：2312235.
[9]Jurgen Brockoller, MD, Julia Kircbbeiner, MD, Jurgen Schmider, MD, et al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and in the outcome of haloperidol treatment [J].Clin Pharmacol Ther,2002,72 (4):4382452.
[10]Henrike Wuttke,MD,Thomas Rau,MD,Roland Heide,BS,et al. Increased freqeuncy of cytochrome P450 2D6 poor metabolizers among patiens with metoprolol2associzationadverse effects [J].Clinical Pharmacology & Therapeutics.2002,72 (4):4302437.
[11]Julia Kircbbeiner, MD, Jurgen BrockmE ller, MD, Ingolf Meineke, PhD, et al. Impact of the CYP2C9 amino acid polymorphisms on glyburide kinetics andon the insulin and glucose response in heathy volunteers [J]. Clin Pharmacol. Ther.2002,72 (4):2862295.
[12]李德淳,朱理璎.药物代谢酶昼夜节律的变化观察与中医学“择时用药”原则探讨[J].中草药,1996,27(8)：4792481.
[13]Lin JH, Lu AYH. Inhibition and Induction of Cytochrome P450 and the Clinical Implications[J]. Clinical Pharmacokinetics,1998,35 (5):3612390.
[14]《药物开发过程中药物代谢／药物相互作用研究(体外研究)》指南
[1]《化学药物杂质研究的技术指导原则》,2005年3月
[2]《化学药物质量控制分析方法验证技术指导原则》,2009年
[3]《化学药物残留溶剂研究的技术指导原则》,2009年
[41《中国药典》2010年版二部,2009年