活性天然产物的合成、衍生物制备及抗肿瘤活性研究
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摘要
双联苄(Bisbibenzyl)是苔藓植物中特有的一类天然多酚类化合物,具有抗真菌、抗微生物、抗氧化、细胞毒、昆虫拒食、植物生长调节和抗血小板凝集等广泛而又显著的生物学活性。近期研究表明,双联苄能够作用于P-糖蛋白、微管蛋白、组织蛋白酶、环氧合酶、诱生型一氧化氮合酶和肝X受体等生物学靶点。迄今为止,已从苔藓植物中发现100余种结构类型新颖且活性优良的双联苄类化合物,可作为新药研究的良好先导化合物。以活性显著的双联苄为目标进行全合成,并在此基础之上对其进行结构改造和修饰对于发现和研制新型药物具有重要意义。
白藜芦醇(Resveratrol)是一种广泛分布于植物界中的非黄酮类多酚化合物,具有与双联苄相似的结构单元。目前白藜芦醇被认为是一种天然的植物抗毒素,并表现出延缓衰老,保护心血管,抗肿瘤和化学预防等多种生物学活性。近十五年的研究表明,白藜芦醇可作用于环氧化酶、脂肪氧化物酶、核因子-kB、醌还原酶、鸟氨酸脱羧酶和芳香化酶等多种生物学靶点,这种多靶点特性使得白藜芦醇具有广泛的活性,但同时导致其很难作为一种高效、专一的药物进行开发和研制,因此以白藜芦醇为先导化合物,对其进行结构修饰、改造并制备衍生物,对发现高选择性、高效能的药物具有重要意义,这也是目前医药学领域内研究的一个重点和热点。
本文以具有多药耐药逆转活性的新型双联苄类化合物Dihydroptychantol A(DHA)为目标,对其进行了全合成研究,并以DHA合成中间体为原料进行结构修饰和改造,在双联苄体系中引入噻唑杂环结构,共制备得到6个衍生物。多药耐药逆转活性测试结果表明部分衍生物对长春新碱耐药细胞株KB/VCR具有显著的耐药逆转活性,逆转倍数(RF)为10.58～13.81,较DHA(RF=3.25)有显著提高。在此基础上,本文对P-糖蛋白与DHA及其衍生物进行了分子模拟研究,探讨了双联苄类化合物在P-糖蛋白中的结合位点和两者之间可能的作用方式,对基于P-糖蛋白的新型多药耐药逆转剂的设计和优化提供了有益的指导和帮助。
本文以具有微管蛋白抑制活性的双联苄类化合物地钱素C(Marchantin C)为目标,首次对其进行了全合成研究,为其生物学和药理学活性的深入研究提供了合成方法和物质保障。另外,本文通过改变地钱素C上酚羟基的数目及苯环间的相互连接位置,设计并合成了24个结构新颖的地钱素C类似物。MTT法体外细胞实验测定了其中8个含酚羟基化合物对U20S(成骨肉瘤细胞)和EYFP(荧光标记微管蛋白的Hela细胞)的细胞毒活性,实验结果表明多数化合物的细胞毒活性优于地钱素C。其中,化合物36对U20S和EYFP细胞的半数抑制浓度(IC50)分别为12.46μM和12.41μM,化合物38的分别为16.62μM和11.71μM。细胞毒活性较地钱素C(IC50值分别为27.42 gM和20.22 gM)有明显改善。
本文最后以白藜芦醇为先导化合物,以芳香化酶(aromatase)为靶点,利用计算机辅助药物设计的手段设计并合成了70个含有不同种类取代基团的反式芪类化合物。芳香化酶抑制活性实验表明,化合物35、104和106对芳香化酶的半数抑制浓度(IC50)分别0.15μM、0.06μM和0.04μM,较白藜芦醇(IC50=80μM)有显著提高。除芳香化酶外,还对醌还原酶2(QR2)、鸟氨酸脱羧酶(ODC)、核因子-kB(NF-kB)和诱生型一氧化氮合酶(iNOS)等与化学预防相关的生物学靶点进行了活性筛选,发现化合物35和47对醌还原酶2具有显著的抑制作用,其IC50值分别为1.7μM和0.27μM,较白藜芦醇(IC50=5.1μM)有显著提高。化合物35和47分别与QR2共结晶复合物的X-射线单晶衍射研究阐明了化合物与靶蛋白之间的作用方式,揭示了酶抑制活性明显优于白藜芦醇的原因,为今后QR2抑制剂的设计与研究提供了可靠的指导和依据。
Bisbibenzyls are a series of phenolic natural products that are found exclusively in bryophytes. These natural products exhibite a variety of biological activities, including 5-lipoxygenase, cyclooxygenase and calmodulin inhibitory effects, and antifungal, antimicrobial, antioxidative, muscle-relaxing, and cytotoxic activities. To date, more than 100 types of bisbibenzyl with excellent biological activity have been discovered from the liverworts and some of them could be the prospective leading comound for the drug discovery. Total synthesis and preparation of derivatives of bisbibenzyls with excellent activity is a good way to develop novel drug.
Resveratrol, with the sturcture similar to bisbibenzyl, is a natural occuring phytotoxin wide spread in continental plant. Resveratrol was found to exhibite versatile biological activities, such as anti-aging, anticancer, cardioprotective, chemopreventive activities. Within the past decade, it has become increasing clear that resveratrol could target on cycloxygenase, lipoxygenase, nuclear factor kappa B, quinone reaductase, ornithine decarboxylase and aromatase. However, this multi-target property of resveratrol lead to the lack of selectivity and potency, and it is very difficult to pinpoint which target is most important for the treatment of a given disease state. The broad-spectrum of activities exhibited by resveratrol can lead to side effects as well. One possible solution to these various problems is to develop resveratrol analogues that exhibit selectivity for only one target with greater potency.
The macrocyclic bisbibenzyl dihydroptychantol A (DHA) was synthesized and showed significant multidrug resistance (MDR) reversing activity in chemoresistant cancer cells. In an attempt to discover more potent MDR reversal agents for efficient cancer chemotherapy, DHA derivatives with thiazole rings were designed and synthesized, and their cytotoxicities and MDR reversal activities were evaluated in adriamycin-resistant K562/A02, vincristine-resistant KB/VCR and their parental cells by MTT assays. Among the tested compouds, the intermediate 20 and the analogues 22,23, and 24 showed potent MDR reversal activities and increased vincristine cytotoxicity in KB/VCR cells, with the reversal fold ranges from 10.58 to 13.81 (10μM), which is stronger than the natural product DHA (RF=3.25). The molecular modeling study reveals the possible binding mode of P-gp with DHA and it's derivatives, which could direct the structure optimization in the further.
The macrocyclic bisbibenzyl marchantin C (MC), a potent microtubulin inhibitor, was synthesized and 24 analogues with various amount of hydroxyl group and different substitutive mode on the phenyl ring were prepared. The cytotoxic activity of 8 phenolic compounds was tested by MTT method. Most analogues exhibite more potent cytotoxicity than marchantin C. The IC50 value of compound 36 on U2OS and EYFP is 12.46 and 12.41μM, respectively; and the IC50 value of compound 38 is 16.62μM and 11.71μM, respectively. Both compounds are much more potent than marchantin C.
A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The design of the new compounds was guided by molecular modeling based on human aromatase (PDB 3eqm). Compounds 35,104 and 106 were shown to be potent aromatase inhibitors (IC50 values 0.15μM,63.3 nM and 40.3 nM, respectively) with inhibitory activity greater than that of resveratrol (IC50 80μM). In addition to aromatase inhibitory activity, compounds 35 and 47 also displayed potent QR2 inhibitory activity (IC501.7 μM and 0.27μM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism QR2 inhibition. The initial biological investigations suggest that these compounds and their analogues merit further investigation as potential chemopreventive agents.
白藜芦醇(Resveratrol)是一种广泛分布于植物界中的非黄酮类多酚化合物,具有与双联苄相似的结构单元。目前白藜芦醇被认为是一种天然的植物抗毒素,并表现出延缓衰老,保护心血管,抗肿瘤和化学预防等多种生物学活性。近十五年的研究表明,白藜芦醇可作用于环氧化酶、脂肪氧化物酶、核因子-kB、醌还原酶、鸟氨酸脱羧酶和芳香化酶等多种生物学靶点,这种多靶点特性使得白藜芦醇具有广泛的活性,但同时导致其很难作为一种高效、专一的药物进行开发和研制,因此以白藜芦醇为先导化合物,对其进行结构修饰、改造并制备衍生物,对发现高选择性、高效能的药物具有重要意义,这也是目前医药学领域内研究的一个重点和热点。
本文以具有多药耐药逆转活性的新型双联苄类化合物Dihydroptychantol A(DHA)为目标,对其进行了全合成研究,并以DHA合成中间体为原料进行结构修饰和改造,在双联苄体系中引入噻唑杂环结构,共制备得到6个衍生物。多药耐药逆转活性测试结果表明部分衍生物对长春新碱耐药细胞株KB/VCR具有显著的耐药逆转活性,逆转倍数(RF)为10.58～13.81,较DHA(RF=3.25)有显著提高。在此基础上,本文对P-糖蛋白与DHA及其衍生物进行了分子模拟研究,探讨了双联苄类化合物在P-糖蛋白中的结合位点和两者之间可能的作用方式,对基于P-糖蛋白的新型多药耐药逆转剂的设计和优化提供了有益的指导和帮助。
本文以具有微管蛋白抑制活性的双联苄类化合物地钱素C(Marchantin C)为目标,首次对其进行了全合成研究,为其生物学和药理学活性的深入研究提供了合成方法和物质保障。另外,本文通过改变地钱素C上酚羟基的数目及苯环间的相互连接位置,设计并合成了24个结构新颖的地钱素C类似物。MTT法体外细胞实验测定了其中8个含酚羟基化合物对U20S(成骨肉瘤细胞)和EYFP(荧光标记微管蛋白的Hela细胞)的细胞毒活性,实验结果表明多数化合物的细胞毒活性优于地钱素C。其中,化合物36对U20S和EYFP细胞的半数抑制浓度(IC50)分别为12.46μM和12.41μM,化合物38的分别为16.62μM和11.71μM。细胞毒活性较地钱素C(IC50值分别为27.42 gM和20.22 gM)有明显改善。
本文最后以白藜芦醇为先导化合物,以芳香化酶(aromatase)为靶点,利用计算机辅助药物设计的手段设计并合成了70个含有不同种类取代基团的反式芪类化合物。芳香化酶抑制活性实验表明,化合物35、104和106对芳香化酶的半数抑制浓度(IC50)分别0.15μM、0.06μM和0.04μM,较白藜芦醇(IC50=80μM)有显著提高。除芳香化酶外,还对醌还原酶2(QR2)、鸟氨酸脱羧酶(ODC)、核因子-kB(NF-kB)和诱生型一氧化氮合酶(iNOS)等与化学预防相关的生物学靶点进行了活性筛选,发现化合物35和47对醌还原酶2具有显著的抑制作用,其IC50值分别为1.7μM和0.27μM,较白藜芦醇(IC50=5.1μM)有显著提高。化合物35和47分别与QR2共结晶复合物的X-射线单晶衍射研究阐明了化合物与靶蛋白之间的作用方式,揭示了酶抑制活性明显优于白藜芦醇的原因,为今后QR2抑制剂的设计与研究提供了可靠的指导和依据。
Bisbibenzyls are a series of phenolic natural products that are found exclusively in bryophytes. These natural products exhibite a variety of biological activities, including 5-lipoxygenase, cyclooxygenase and calmodulin inhibitory effects, and antifungal, antimicrobial, antioxidative, muscle-relaxing, and cytotoxic activities. To date, more than 100 types of bisbibenzyl with excellent biological activity have been discovered from the liverworts and some of them could be the prospective leading comound for the drug discovery. Total synthesis and preparation of derivatives of bisbibenzyls with excellent activity is a good way to develop novel drug.
Resveratrol, with the sturcture similar to bisbibenzyl, is a natural occuring phytotoxin wide spread in continental plant. Resveratrol was found to exhibite versatile biological activities, such as anti-aging, anticancer, cardioprotective, chemopreventive activities. Within the past decade, it has become increasing clear that resveratrol could target on cycloxygenase, lipoxygenase, nuclear factor kappa B, quinone reaductase, ornithine decarboxylase and aromatase. However, this multi-target property of resveratrol lead to the lack of selectivity and potency, and it is very difficult to pinpoint which target is most important for the treatment of a given disease state. The broad-spectrum of activities exhibited by resveratrol can lead to side effects as well. One possible solution to these various problems is to develop resveratrol analogues that exhibit selectivity for only one target with greater potency.
The macrocyclic bisbibenzyl dihydroptychantol A (DHA) was synthesized and showed significant multidrug resistance (MDR) reversing activity in chemoresistant cancer cells. In an attempt to discover more potent MDR reversal agents for efficient cancer chemotherapy, DHA derivatives with thiazole rings were designed and synthesized, and their cytotoxicities and MDR reversal activities were evaluated in adriamycin-resistant K562/A02, vincristine-resistant KB/VCR and their parental cells by MTT assays. Among the tested compouds, the intermediate 20 and the analogues 22,23, and 24 showed potent MDR reversal activities and increased vincristine cytotoxicity in KB/VCR cells, with the reversal fold ranges from 10.58 to 13.81 (10μM), which is stronger than the natural product DHA (RF=3.25). The molecular modeling study reveals the possible binding mode of P-gp with DHA and it's derivatives, which could direct the structure optimization in the further.
The macrocyclic bisbibenzyl marchantin C (MC), a potent microtubulin inhibitor, was synthesized and 24 analogues with various amount of hydroxyl group and different substitutive mode on the phenyl ring were prepared. The cytotoxic activity of 8 phenolic compounds was tested by MTT method. Most analogues exhibite more potent cytotoxicity than marchantin C. The IC50 value of compound 36 on U2OS and EYFP is 12.46 and 12.41μM, respectively; and the IC50 value of compound 38 is 16.62μM and 11.71μM, respectively. Both compounds are much more potent than marchantin C.
A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The design of the new compounds was guided by molecular modeling based on human aromatase (PDB 3eqm). Compounds 35,104 and 106 were shown to be potent aromatase inhibitors (IC50 values 0.15μM,63.3 nM and 40.3 nM, respectively) with inhibitory activity greater than that of resveratrol (IC50 80μM). In addition to aromatase inhibitory activity, compounds 35 and 47 also displayed potent QR2 inhibitory activity (IC501.7 μM and 0.27μM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism QR2 inhibition. The initial biological investigations suggest that these compounds and their analogues merit further investigation as potential chemopreventive agents.
引文
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