呋喃香豆素类化合物无紫外光辅助照射时抗肿瘤活性低, 为提高其正常情况下的抗肿瘤活性, 依据“最小嵌入”假说对其进行结构改造。 把呋喃香豆素结构中的呋喃环拆分出来, 使其与香豆素由原来稠环相并的结合方式转变为通过化学键相连, 得到合成简化的类呋喃香豆素。 利用DNA熔解曲线、 吸收光谱、 荧光发射光谱和粘度测试考察了这些类呋喃香豆素与DNA的相互作用。 综合DNA溶解曲线、 光谱法和粘度测试的结果, 推测除目标产物5b是一DNA嵌入剂外, 其他化合物嵌入DNA能力下降, 5a以部分嵌入方式与DNA结合, 5c和5d是通过极为少见、 鲜有报道的“桥型结构”与DNA相结合。 利用“罗丹明B蛋白染色法”考察了目标化合物的体外细胞毒性, 测试结果显示, 与对照品补骨脂素相比这些化合物对肿瘤细胞体外生长抑制作用明显增强, 并且非经典嵌入结合的化合物活性增强更明显。 该研究拓展了“最小嵌入”假说的应用范围, 同时为呋喃香豆素类化合物结构改造提供了依据。

Furocoumarin shows some antitumor activity when it is radiated by the UV light. In order to improve the antitumor activity of furocoumarin under standard environment conditions, the “minimal DNA-intercalating” hypothesis was firstly introduced to the structural modification of furocoumarin, which resulted in the design of pseudo-furocoumarin.The pseudo-furocoumarin was synthesized by two-step reaction including Pechmann reaction catalyzed by conc. H2SO4 and Suzuki coupling reaction catalyzed by Pd(PPh3)4. The structural character of the pseudo-furocoumarin is that the bonding mode of furan ring fused to the coumarin is replaced by a chemical single bond between furan ring and coumarin. The interaction of the pseudo-furocoumarin with calf thymus DNA (CT-DNA) has been respectively investigated by using DNA melting curve, UV-Vis absorption spectra, fluorescence spectra and viscosity titration, and the modes of DNA-binding for the pseudo-furocoumarin have been proposed. Based on the results of DNA melting curve, spectra and viscosity titration, it was suggested that 5a and 5b bind to DNA by the partial intercalation and classical intercalation, respectively. The DNA-binding behaviors of 5c and 5d have been rarely reported in literature and may be interpreted in terms of bridge-structure. All target compounds, except 5b, show a decreasing capability of intercalation to DNA. Further, the antiproliferative activities of the pseudo-furocoumarin on human lung adenocarcinoma (A549), human breast cancer (MCF-7) and human ovarian carcinoma cell line (SKOV-3) in vitro were evaluated using the sulforhodamine B (SRB) protein statin assay. All pseudo-furocoumarin exhibited an improved anti-proliferative activity as compared with the control compound psoralen (PS, a linear furocoumarin). Interestingly the pseudo-furocoumarin binding to DNA by a non-classical intercalation mode showed a stronger anti-proliferative activity than PS. The present study extended the applied areas of “minimal DNA-intercalating” hypothesis, and provided a method for the structural modification of furocoumarin as well.