新颖萘酰亚胺类抗肿瘤剂的设计合成与生物性能
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摘要
本论文基于萘酰亚胺活性结构,设计合成了四类新型抗肿瘤药物先导,评价了其对7种肿瘤细胞株(HeLa、A549、P388、HL-60、MCF-7、HCT-8、A375)的细胞毒性,以及对DNA嵌入、BSA结合、细胞周期阻滞、凋亡诱导和COX-2酶结合等性能。
第一部分研究了氨基酸-萘酰亚胺加合物的抗肿瘤性能。通过在侧链引入具有生物功能的亮氨酸替代传统的N,N-二甲基氨基乙二胺,设计合成了6个目标化合物。细胞毒性测试结果表明该系列化合物具有中等强度的抗肿瘤活性,IC50值为10-6-10-5M,而化合物8a-c对MCF-7细胞具有选择性毒性；BSA结合实验表明,6-位苯硫基乙基氨基取代基可能对其MCF-7细胞选择性毒性有一定贡献；ctDNA滴定和粘度实验表明,该类化合物为DNA嵌入剂。
第二部分研究了Amonafide类似物的抗肿瘤和促凋亡性能。通过对4-位氨基取代基的疏水性结构修饰,设计合成了10个目标化合物。细胞毒性测试结果表明该系列化合物具有中等强度的抗肿瘤活性,IC50值为10-6-10-5 M; FACS实验表明该系列化合物具有显著的细胞周期阻滞性能,并能有效地诱导HL-60细胞凋亡；Annexin V-FITC/PI实验进一步确证,化合物5b、7b、7e以浓度依赖的方式有效地诱导HL-60细胞凋亡；生物学机理研究表明：化合物5a以不依赖于p53的方式通过调节Cyclin B1、Cdkl的转录水平,减少Cyclin B1-Cdkl复合物的含量,将细胞阻滞在G2期；通过阻抑PI3K/Akt途径中p85和Akt的磷酸化激活作用,抑制NF-κB核转位,下调Bcl-2蛋白的表达并呈剂量依赖性,上调Bax的表达,上调Caspase-3、-9的活性,而最终诱导细胞凋亡。
第三部分研究了二苯基烯丙哌嗪苯甲酸-萘酰亚胺衍生物的抗肿瘤和促凋亡性能。通过在萘酰亚胺的2-位和6-位同时引入不同的生物活性单元,设计合成了9个目标化合物。细胞毒性测试表明该系列化合物具有中等强度的抗肿瘤活性,IC5o值为10-6-10-5M;化合物12e表现出独特的选择性的MCF-7细胞毒性；FACS实验表明,该系列化合物表现出显著的细胞周期阻滞性能,并能有效地诱导HL-60细胞凋亡；Annexin V-FITC/PI实验进一步确证,化合物12b和13d以浓度依赖的方式有效地诱导HL-60细胞凋亡。
第四部分研究了吲哚美辛-萘酰亚胺加合物的抗肿瘤、促凋亡、乏氧以及COX-2酶结合等性能。基于多靶点药物设计的特点,将吲哚美辛与萘酰亚胺进行加合,设计合成了4个目标化合物。细胞毒性测试结果表明该系列化合物具有一定程度的抗肿瘤活性,并能显著诱导HeLa细胞凋亡；酰胺衍生物4c和4d表现出比其酯类衍生物较好的细胞毒性和促凋亡活性,而酯类衍生物4a和4b则表现出比其酰胺衍生物更好的乏氧选择性细胞毒性；酶结合实验表明,目标化合物与COX-2酶之间具有一定程度的作用。
In the dissertation, four kinds of naphthalimide derivatives, based on the lead compound of Amonafide, were designed and synthesized. Their antitumor activities were evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8, A375 cancer cell lines in vitro. The properties of their DNA-intercalating, BSA binding, cell cycle arrest and induction of apoptosis, were also systematically studied.
The first section described the antitumor activities of naphthalimide-amino acid conjugates. Six target compounds were designed and synthesized by conjugating naphthalimide scaffold with flexible leucine moiety as side chain instead of conventional N,N-dimethyl-aminoethylenediamine functional group. The preliminary results showed that most of the derivatives had moderate antitumor activities with the IC50 values of 10"6-10-5 M. More importantly, compounds 8a-c exhibited exclusive antitumor activities against MCF-7 cell line. BSA binding experiment implied that hydrophobic substituents of compounds 8a-c proved to be a key structural unit for their binding abilities to BSA, which might provide some suggestions on the understanding of their exclusive antitumor selectivity against MCF-7 cell line. DNA binding experiments indicated that these derivatives behaved as DNA intercalating agents.
The second section focused on the antitumor and pro-apoptotic function of Amonafide analogues. Ten target compounds were designed and synthesized by modification of the position-6 of naphthalimide by hydrophobic substituents. The preliminary results showed that most of the derivatives had comparable antitumor activities over Amonafide with the IC50 values of 10-6-10-5 M. More importantly, flow cytometric analysis indicated that the derivatives, such as compounds 5b、7b、7e, could effectively induce G2/M arrest and progress to apoptosis in a dose-dependent manner in HL-60 cell line after double staining with annexin V-FITC and propidium iodide. Detailed biological experiment exhibited that compound 5a induced G2/M phase growth arrest through inhibiting PI3K/Akt pathway and DNA fragmentation. Not only the expression levels of protein Cyclin B1, Cdkl changed in response to compound 5a treatment in HL-60 cells, but also we observed the inhibition of NF-κB nuclear translocation, up-regulation of Bax and down-regulation of Bcl-2. The activities of caspase-3,-9 increased, indicating that the mitochondrial pathway was involved in the apoptosis signal pathway. The results also showed that the phosphorylation of p85/PI3 K and Akt decreased following compound 5a treatment.
The third section studied on the alternative modification of naphthalimide scaffold and evaluated their antitumor and apoptosis-inducing function. Nine target compounds were designed and synthesized by connecting naphthalimide and 4-(4-(3,3-diphenylallyl)piperazin-1-yl)benzoic acid moiety with different functional linkers, ethanolamine and sulfanilamide. The preliminary results showed that most of the derivatives had comparable antitumor activities over Amonafide with the IC50 values of 10-6-10-5 M. Interestingly, compound 12e exhibited the exclusive antitumor activity against MCF-7 among the tested cancer cell lines. More importantly, flow cytometric analysis indicated that these derivatives, such as compounds 12b and 13d, could effectively induce G2/M arrest and progress to apoptosis in a dose-dependent manner in HL-60 cell line after double staining with annexin V-FITC and propidium iodide. The present work provided a novel class of naphthalimide-based derivatives with potent apoptosis-inducing and improved antitumor activity for further optimization.
The fourth section centered on the conjugation of indomethacin and naphthalimide scaffold, and evaluated their hypoxic/oxic cytotoxicity, apoptosis-inducing function and combination with COX-2. Four target compounds were designed and synthesized. The preliminary results showed that the derivatives had some antitumor activities and obvious apoptosis-inducing function. More importantly, amide derivatives 4c and 4d, exhibited the superior oxic cytotoxic and proapoptotic activities over their ester derivatives; while the ester derivatives 4a and 4b, showed excellent hypoxic cytotoxic activity. COX-2 titration experiments demonstrated that there was interaction between the target compound and COX-2 to some extent, which could provide some explanation for their special biological activity. The conjugates described herein represented powerful tools for the investigation of a novel class of selective inhibitors of COX-2.
第一部分研究了氨基酸-萘酰亚胺加合物的抗肿瘤性能。通过在侧链引入具有生物功能的亮氨酸替代传统的N,N-二甲基氨基乙二胺,设计合成了6个目标化合物。细胞毒性测试结果表明该系列化合物具有中等强度的抗肿瘤活性,IC50值为10-6-10-5M,而化合物8a-c对MCF-7细胞具有选择性毒性；BSA结合实验表明,6-位苯硫基乙基氨基取代基可能对其MCF-7细胞选择性毒性有一定贡献；ctDNA滴定和粘度实验表明,该类化合物为DNA嵌入剂。
第二部分研究了Amonafide类似物的抗肿瘤和促凋亡性能。通过对4-位氨基取代基的疏水性结构修饰,设计合成了10个目标化合物。细胞毒性测试结果表明该系列化合物具有中等强度的抗肿瘤活性,IC50值为10-6-10-5 M; FACS实验表明该系列化合物具有显著的细胞周期阻滞性能,并能有效地诱导HL-60细胞凋亡；Annexin V-FITC/PI实验进一步确证,化合物5b、7b、7e以浓度依赖的方式有效地诱导HL-60细胞凋亡；生物学机理研究表明：化合物5a以不依赖于p53的方式通过调节Cyclin B1、Cdkl的转录水平,减少Cyclin B1-Cdkl复合物的含量,将细胞阻滞在G2期；通过阻抑PI3K/Akt途径中p85和Akt的磷酸化激活作用,抑制NF-κB核转位,下调Bcl-2蛋白的表达并呈剂量依赖性,上调Bax的表达,上调Caspase-3、-9的活性,而最终诱导细胞凋亡。
第三部分研究了二苯基烯丙哌嗪苯甲酸-萘酰亚胺衍生物的抗肿瘤和促凋亡性能。通过在萘酰亚胺的2-位和6-位同时引入不同的生物活性单元,设计合成了9个目标化合物。细胞毒性测试表明该系列化合物具有中等强度的抗肿瘤活性,IC5o值为10-6-10-5M;化合物12e表现出独特的选择性的MCF-7细胞毒性；FACS实验表明,该系列化合物表现出显著的细胞周期阻滞性能,并能有效地诱导HL-60细胞凋亡；Annexin V-FITC/PI实验进一步确证,化合物12b和13d以浓度依赖的方式有效地诱导HL-60细胞凋亡。
第四部分研究了吲哚美辛-萘酰亚胺加合物的抗肿瘤、促凋亡、乏氧以及COX-2酶结合等性能。基于多靶点药物设计的特点,将吲哚美辛与萘酰亚胺进行加合,设计合成了4个目标化合物。细胞毒性测试结果表明该系列化合物具有一定程度的抗肿瘤活性,并能显著诱导HeLa细胞凋亡；酰胺衍生物4c和4d表现出比其酯类衍生物较好的细胞毒性和促凋亡活性,而酯类衍生物4a和4b则表现出比其酰胺衍生物更好的乏氧选择性细胞毒性；酶结合实验表明,目标化合物与COX-2酶之间具有一定程度的作用。
In the dissertation, four kinds of naphthalimide derivatives, based on the lead compound of Amonafide, were designed and synthesized. Their antitumor activities were evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8, A375 cancer cell lines in vitro. The properties of their DNA-intercalating, BSA binding, cell cycle arrest and induction of apoptosis, were also systematically studied.
The first section described the antitumor activities of naphthalimide-amino acid conjugates. Six target compounds were designed and synthesized by conjugating naphthalimide scaffold with flexible leucine moiety as side chain instead of conventional N,N-dimethyl-aminoethylenediamine functional group. The preliminary results showed that most of the derivatives had moderate antitumor activities with the IC50 values of 10"6-10-5 M. More importantly, compounds 8a-c exhibited exclusive antitumor activities against MCF-7 cell line. BSA binding experiment implied that hydrophobic substituents of compounds 8a-c proved to be a key structural unit for their binding abilities to BSA, which might provide some suggestions on the understanding of their exclusive antitumor selectivity against MCF-7 cell line. DNA binding experiments indicated that these derivatives behaved as DNA intercalating agents.
The second section focused on the antitumor and pro-apoptotic function of Amonafide analogues. Ten target compounds were designed and synthesized by modification of the position-6 of naphthalimide by hydrophobic substituents. The preliminary results showed that most of the derivatives had comparable antitumor activities over Amonafide with the IC50 values of 10-6-10-5 M. More importantly, flow cytometric analysis indicated that the derivatives, such as compounds 5b、7b、7e, could effectively induce G2/M arrest and progress to apoptosis in a dose-dependent manner in HL-60 cell line after double staining with annexin V-FITC and propidium iodide. Detailed biological experiment exhibited that compound 5a induced G2/M phase growth arrest through inhibiting PI3K/Akt pathway and DNA fragmentation. Not only the expression levels of protein Cyclin B1, Cdkl changed in response to compound 5a treatment in HL-60 cells, but also we observed the inhibition of NF-κB nuclear translocation, up-regulation of Bax and down-regulation of Bcl-2. The activities of caspase-3,-9 increased, indicating that the mitochondrial pathway was involved in the apoptosis signal pathway. The results also showed that the phosphorylation of p85/PI3 K and Akt decreased following compound 5a treatment.
The third section studied on the alternative modification of naphthalimide scaffold and evaluated their antitumor and apoptosis-inducing function. Nine target compounds were designed and synthesized by connecting naphthalimide and 4-(4-(3,3-diphenylallyl)piperazin-1-yl)benzoic acid moiety with different functional linkers, ethanolamine and sulfanilamide. The preliminary results showed that most of the derivatives had comparable antitumor activities over Amonafide with the IC50 values of 10-6-10-5 M. Interestingly, compound 12e exhibited the exclusive antitumor activity against MCF-7 among the tested cancer cell lines. More importantly, flow cytometric analysis indicated that these derivatives, such as compounds 12b and 13d, could effectively induce G2/M arrest and progress to apoptosis in a dose-dependent manner in HL-60 cell line after double staining with annexin V-FITC and propidium iodide. The present work provided a novel class of naphthalimide-based derivatives with potent apoptosis-inducing and improved antitumor activity for further optimization.
The fourth section centered on the conjugation of indomethacin and naphthalimide scaffold, and evaluated their hypoxic/oxic cytotoxicity, apoptosis-inducing function and combination with COX-2. Four target compounds were designed and synthesized. The preliminary results showed that the derivatives had some antitumor activities and obvious apoptosis-inducing function. More importantly, amide derivatives 4c and 4d, exhibited the superior oxic cytotoxic and proapoptotic activities over their ester derivatives; while the ester derivatives 4a and 4b, showed excellent hypoxic cytotoxic activity. COX-2 titration experiments demonstrated that there was interaction between the target compound and COX-2 to some extent, which could provide some explanation for their special biological activity. The conjugates described herein represented powerful tools for the investigation of a novel class of selective inhibitors of COX-2.
引文
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