摘要
根据以DNA为靶点的抗肿瘤药物的作用机理,分别以具有平面缺电子结构的1,8-萘酰亚胺和苯并[c,d]吲哚-2(1H)-酮为母体,设计合成了三个系列的DNA靶向分子,所有的化合物经过了核磁共振、高分辨质谱的分析鉴定,并对化合物的光谱性质、DNA嵌插能力、DNA切割能力和体外抗肿瘤活性进行研究。
设计合成了系列新型的噻二唑并萘酰亚胺类化合物。通过紫外-可见光谱、荧光光谱、粘度测试和圆二色谱结果均显示噻二唑并萘酰亚胺类化合物具有良好的DNA嵌入能力。N-(N’,N’-二甲基胺基乙基)-2,1,3-噻二唑并萘酰亚胺S1与DNA嵌入常数Kb为2.83×105mol-1·L新型的噻二唑并萘酰亚胺类化合物与CT DNA作用的圆二色谱表明,它们能以经典的嵌插方式与DNA结合,使DNA正峰增加,负峰减少,化合物可以插入到DNA碱基对中,通过π电子的相互作用,增大碱基堆积程度。pBR322质粒DNA切断测试证明化合物具有一定的DNA切割能力,连接N,N-二甲基丙二胺侧链的化合物切割效果最佳。体外抗肿瘤活性测试中,带有柔性胺基侧链的新型的噻二唑并萘酰亚胺类化合物对所选的人肝癌细胞7721,人乳腺癌细胞MCF-7,人宫颈癌细胞Hela,人白血病细胞HL60和人肺腺癌细胞A549细胞都有良好的抑制活性。
合成了一系列未见报道的苯并[c,d]吲哚-2(H)-酮新结构衍生物。通过Knoevenagel Condensation缩合得到α,β-不饱和化合物。该系列衍生物与DNA的结合强度较高,其与DNA结合常数Kb为1.65×105mol-1·L;与DNA主要发生了嵌插结合,均具有一定的DNA切割性能,其中以连接丙炔基侧链化合物效果最佳,化合物AC1-6都能将超螺旋DNA切断成Ⅲ型；AC6对MCF-7(人体乳腺癌)的IC5o值能达到nM级。对于萘酰亚胺衍生物的抗肿瘤作用,通常萘酰亚胺侧链为氨基侧链才有效果,但是对于我们合成的系列化合物,由于分子的强缺电特性,无侧链氨基化合物也具有突出的抗肿瘤活性。
设计、合成了两个系列含1,2,3-三唑环萘酰亚胺类DNA嵌入剂。该类化合物具有较强的DNA嵌入性能,其嵌入常数数量级在105mol-1·L以上。随着化合物浓度的增大,其与CT DNA的作用模式从嵌入模式渐渐转变成静电堆积模式。具有较强的DNA光敏损伤活性。化合物具有明显的体外抑制肿瘤细胞生长活性。通过荧光光谱法研究了化合物与CT DNA的相互作用,表明该化合物具有较强的DNA嵌入性能,其嵌入常数为3.51×105mol-1·L。该系列化合物具有一定的光敏损伤活性。带有N,N二甲基乙二胺侧链的化合物是最有效的抗肿瘤化合物,分别是先导化合物Amonafide对应三个细胞株抗肿瘤活性的5.6倍,2.4倍和8.5倍。F1-5系列化合物对7721细胞抗肿瘤活性高于人乳腺癌细胞株MCF-7和宫颈癌细胞Hela细胞株。
Based on series of triazoles containing heterocyclic and naphthalimides compounds were designed and synthesized and confirmed by NMRJR and HRMS. Their spectra properties, DNA intercalative, antitumor and DNA photo-damaging activities were evaluated.
Novel2,1,3-thiadiazole fused1,8-naphthalimide derivatives had been synthesized and the results of UV-Vis spectra, Fluorescence spectra, CD spectra and viscosity measurement all showed that the compounds had good DNA binding ability.2,1,3-thiadiazole fused1,8-naphthalimide derivatives S1binding constant could reach2.83×105mol-1·L. The change appeared in the CD spectra of DNA when incubated with2,1,3-thiadiazole fused1,8-naphthalimide derivatives S1and2,1,3-thiadiazole fused1,8-naphthalimide derivatives S4illustrated that the compounds interacted with DNA by the classical intercalating mode, making the positive band increase and the negative band decrease. All the2,1,3-thiadiazole fused1,8-naphthalimide derivatives compounds could cleave supercoiled plasmid DNA, especially S3. S1-4,,bearing flexible amine side chains, showed excellent cytotoxicity to the selected MCF-7,7721, Hela, A549and HL60cell lines.
The derivatives of Benzo[c, d]indol-2(H)-one have been synthesized. Their DNA bonding properties were evaluated through UV-Vis spectra, Fluorescence spectra and CD spectra combined with viscosity measurement. The result showed that compounds can efficiently intercalate base pairs of CT DNA, while AC3's bonding constant is Kb=1.65×105mol-1·L. DNA photo-damaging assay were taken with pBR322plasmid. All the compounds are efficient to cleave super-coiled DNA, while AC1-6can photo-cleave super-coiled DNA into linear fragments. AC6showed that this compound exhibited high antitumor activities, IC50of compound against MCF-7cell reached3nM.
Two series of triazol-1,8-naphthalimide derivatives were designed and synthesized via "Click Chemistry". Their spectra properties, DNA intercalative, DNA photo-damaging and antitumor activities were evaluated. Titration CD spectra of DNA by compounds illustrated that the mode of compounds interacted with DNA changed from intercalation to aggregation with the concentration increased. In particular, compound bearing N,N-dimethylethylenediamine with the values of IC50against three cell lines was5.6-fold,2.4-fold,and8.5-fold lower than that of Amonafide, and other compounds bearing aminoalkyl side chains were all more potent than Amonafide. DNA photo-damaging assay showed that these compounds could effectively cleave supercoiled DNA. The compounds were more toxic against7721than MCF-7and Hela cells.
引文
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