新苊并杂环衍生物的合成、光谱及作为DNA靶向分子的研究
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摘要
以高度缺电子的8-氧-8H-苊并[1,2-b]吡咯-9-腈为前体,通过芳香亲核氢取代反应,设计合成了一系列3位氨基、羟基和烷硫基单取代产物,并且得到了氨基单取代的异构体6位氨基取代产物和罕见的3,6-二氨基氢取代产物。研究了8-氧-8H-苊并[1,2-b]吡咯-9-腈与不同亲核试剂的反应活性,发现它有以下的特点:存在两个氢取代活性位点;两个氢可以同时被环状仲胺取代;与氮、氧、硫等不同亲核试剂都能发生氢取代反应。
通过对8-氧-8H-苊并[1,2-b]吡咯-9-腈进行结构改造,得到了溶解性更好的新的8-氧-8H-苊并[1,2-b]吡咯-9-甲酸酯前体。腈基改造为酯基后,体系仍然高度缺电子,可以与胺亲核试剂发生芳香氢取代反应。由此,设计合成了两个系列3位氨基取代的8-氧-8H-苊并[1,2-b]吡咯-9-甲酸酯衍生物。
研究了8-氧-8H-苊并[1,2-b]吡咯-9-甲酸甲酯的3位伯胺基取代物的紫外吸收和荧光光谱。发现它的吸收光谱比具有相同取代基的8-氧-8H-苊并[1,2-b]吡咯-9-腈衍生物红移17-20nm左右,而发射光谱红移14-17nm左右(>600nm),荧光量子产率降低。研究了8-氧-8H-苊并[1,2-b]吡咯-9-腈(甲酸甲酯)的3位仲胺基取代衍生物在不同极性溶剂中的紫外吸收和荧光光谱,发现它与伯胺基取代化合物的光谱有明显的不同,溶剂极性对吸收光谱和荧光量子产率的影响很大,斯托克斯位移从10-20nm增大至60-90nm,这可能是由于存在ICT(分子内电荷转移)激发态造成的。
通过琼脂糖凝胶电泳、紫外可见光谱、荧光光谱、DNA熔解温度曲线、圆二色谱和细胞抑制试验等方法研究了8-氧-8H-苊并[1,2-b]吡咯-9-腈(甲酸酯)类化合物与DNA的相互作用和抗肿瘤活性。结果表明,具有N,N-二烷基和N-甲基-哌嗪基侧链的化合物与CT DNA发生强烈的相互作用,表观结合常数达到10~5-10~6数量级。其中化合物1-1在长波长(λ>400nm)激发下产生单线态氧切割M13 mp18单链环形DNA,最低作用浓度50μM。化合物1-1可以通过表面堆积和嵌入两种方式与CT DNA作用。以HeLa人宫颈癌细胞,A549人肺癌细胞和P388小鼠白血病细胞为靶细胞的体外抑制实验结果表明,能与DNA强烈作用的带有N,N-二烷基侧链取代基的化合物具有较高的细胞毒性,其IC_(50)值达到10~(-8)-10~(-6)μM。且分子中没有N,N-二烷基侧链取代基的大部分化合
8-Oxo-8H-acenaphtho[l,2-b]pyrrole-9-carbonitrile, a flat and highly electron-deficient heteroaromatic compound, was used as precursor to synthesize a series of amino, hydroxyl and dodecylsulfanyl mono-substituted derivatives at 3-position through nucleophilic aromatic substitution of hydrogen (NASH) reaction. 6-Amino substituted derivatives were obtained as the isomers of 3-substituted products. It can be concluded from unusual characteristics for NASH reactivity of the precursor that there were two active sites for NASH reaction in one molecule;two hydrogen atoms in one aromatic conjugation system could be replaced simultaneously;NASH reaction with different nucleophiles (nitrogen, hydroxy group, sulfur) could be happened also.8-Oxo-8//-acenaphtho[l,2-b]pyrrole-9-carboxylic acid esters with improved solubility were obtained from 8-oxo-8H-acenaphtho[l,2-b]pyrrole-9-carbonitrile, and the highly electron-deficient feature was kept in these novel precursors. So a series of 3-substituted derivatives of the ester precursors were synthesized by NASH reaction with amines.Compared with that of the carbonitrile precursor with primary amine substituents at 3-position, the maximum wavelength for the derivatives of ester precursors were red-shifted about 17-20 nm and 14-17 nm in UV-Vis absorption and emission spectra, respectively, and fluorescence quantum yields were decreased. There existed significant difference in UV-Vis and emission spectra between the derivatives with 3-alicyclic secondary amine substituents and those with 3-primary amine substituents. The maximum wavelength of UV-vis and the fluorescence quantum yield were mainly depended on the polarity of solvents and a large Stokes shift (60-90 nm) was obtained, which could be attributed to the excited-state intramolecular charge transfer (ICT).Interaction with DNA and antitumor abilities for 8-oxo-8H-acenaphtho[l,2-b]pyrrole-9-carbonitrile(carboxylic acid ester) and their derivatives were evaluated by agarose gel electrophoresis, UV-Vis absorption and fluorescence spectrum, DNA melt curves, circular
dichroism (CD) spectroscopy, cytotoxicity experience etc. The results demonstrated that the compounds with N-dialkyl group and N-methyl-piperazinyl side chain could bind strongly with CT DNA and the binding constants are in the order of 105-106. Under the irradiation of long wavelength light (A. > 400 nm), compound 1-1 could be used to cleave Ml3 mpl8 single strand circular DNA by generating singlet oxygen, the lowest effective concentration is 50 uM. There were two different interaction mechanisms (intercalation and stacking on surface) involved in the interaction process of compound 1-1 with CT DNA. The inhibitory test against HeLa, A549 and P388 cell lines in vitro showed that the compounds with N-dialkyl group and N-methyl-piperazinyl side chain exhibited higher activity and the IC50 values are in the range of 10" -10" M. Moreover, those compounds without N-dialkyl group basic side chain showed moderate antitumor activity unexpectedly, especially for compound 1-9 with thiomorpholinyl substituent, the IC50 value against HeLa cell is 1.7><1O"5 M. Isotope incorporation experiment of compound 1-9 showed that it disturbed the synthesis of DNA and RNA.
通过对8-氧-8H-苊并[1,2-b]吡咯-9-腈进行结构改造,得到了溶解性更好的新的8-氧-8H-苊并[1,2-b]吡咯-9-甲酸酯前体。腈基改造为酯基后,体系仍然高度缺电子,可以与胺亲核试剂发生芳香氢取代反应。由此,设计合成了两个系列3位氨基取代的8-氧-8H-苊并[1,2-b]吡咯-9-甲酸酯衍生物。
研究了8-氧-8H-苊并[1,2-b]吡咯-9-甲酸甲酯的3位伯胺基取代物的紫外吸收和荧光光谱。发现它的吸收光谱比具有相同取代基的8-氧-8H-苊并[1,2-b]吡咯-9-腈衍生物红移17-20nm左右,而发射光谱红移14-17nm左右(>600nm),荧光量子产率降低。研究了8-氧-8H-苊并[1,2-b]吡咯-9-腈(甲酸甲酯)的3位仲胺基取代衍生物在不同极性溶剂中的紫外吸收和荧光光谱,发现它与伯胺基取代化合物的光谱有明显的不同,溶剂极性对吸收光谱和荧光量子产率的影响很大,斯托克斯位移从10-20nm增大至60-90nm,这可能是由于存在ICT(分子内电荷转移)激发态造成的。
通过琼脂糖凝胶电泳、紫外可见光谱、荧光光谱、DNA熔解温度曲线、圆二色谱和细胞抑制试验等方法研究了8-氧-8H-苊并[1,2-b]吡咯-9-腈(甲酸酯)类化合物与DNA的相互作用和抗肿瘤活性。结果表明,具有N,N-二烷基和N-甲基-哌嗪基侧链的化合物与CT DNA发生强烈的相互作用,表观结合常数达到10~5-10~6数量级。其中化合物1-1在长波长(λ>400nm)激发下产生单线态氧切割M13 mp18单链环形DNA,最低作用浓度50μM。化合物1-1可以通过表面堆积和嵌入两种方式与CT DNA作用。以HeLa人宫颈癌细胞,A549人肺癌细胞和P388小鼠白血病细胞为靶细胞的体外抑制实验结果表明,能与DNA强烈作用的带有N,N-二烷基侧链取代基的化合物具有较高的细胞毒性,其IC_(50)值达到10~(-8)-10~(-6)μM。且分子中没有N,N-二烷基侧链取代基的大部分化合
8-Oxo-8H-acenaphtho[l,2-b]pyrrole-9-carbonitrile, a flat and highly electron-deficient heteroaromatic compound, was used as precursor to synthesize a series of amino, hydroxyl and dodecylsulfanyl mono-substituted derivatives at 3-position through nucleophilic aromatic substitution of hydrogen (NASH) reaction. 6-Amino substituted derivatives were obtained as the isomers of 3-substituted products. It can be concluded from unusual characteristics for NASH reactivity of the precursor that there were two active sites for NASH reaction in one molecule;two hydrogen atoms in one aromatic conjugation system could be replaced simultaneously;NASH reaction with different nucleophiles (nitrogen, hydroxy group, sulfur) could be happened also.8-Oxo-8//-acenaphtho[l,2-b]pyrrole-9-carboxylic acid esters with improved solubility were obtained from 8-oxo-8H-acenaphtho[l,2-b]pyrrole-9-carbonitrile, and the highly electron-deficient feature was kept in these novel precursors. So a series of 3-substituted derivatives of the ester precursors were synthesized by NASH reaction with amines.Compared with that of the carbonitrile precursor with primary amine substituents at 3-position, the maximum wavelength for the derivatives of ester precursors were red-shifted about 17-20 nm and 14-17 nm in UV-Vis absorption and emission spectra, respectively, and fluorescence quantum yields were decreased. There existed significant difference in UV-Vis and emission spectra between the derivatives with 3-alicyclic secondary amine substituents and those with 3-primary amine substituents. The maximum wavelength of UV-vis and the fluorescence quantum yield were mainly depended on the polarity of solvents and a large Stokes shift (60-90 nm) was obtained, which could be attributed to the excited-state intramolecular charge transfer (ICT).Interaction with DNA and antitumor abilities for 8-oxo-8H-acenaphtho[l,2-b]pyrrole-9-carbonitrile(carboxylic acid ester) and their derivatives were evaluated by agarose gel electrophoresis, UV-Vis absorption and fluorescence spectrum, DNA melt curves, circular
dichroism (CD) spectroscopy, cytotoxicity experience etc. The results demonstrated that the compounds with N-dialkyl group and N-methyl-piperazinyl side chain could bind strongly with CT DNA and the binding constants are in the order of 105-106. Under the irradiation of long wavelength light (A. > 400 nm), compound 1-1 could be used to cleave Ml3 mpl8 single strand circular DNA by generating singlet oxygen, the lowest effective concentration is 50 uM. There were two different interaction mechanisms (intercalation and stacking on surface) involved in the interaction process of compound 1-1 with CT DNA. The inhibitory test against HeLa, A549 and P388 cell lines in vitro showed that the compounds with N-dialkyl group and N-methyl-piperazinyl side chain exhibited higher activity and the IC50 values are in the range of 10" -10" M. Moreover, those compounds without N-dialkyl group basic side chain showed moderate antitumor activity unexpectedly, especially for compound 1-9 with thiomorpholinyl substituent, the IC50 value against HeLa cell is 1.7><1O"5 M. Isotope incorporation experiment of compound 1-9 showed that it disturbed the synthesis of DNA and RNA.
引文
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