目的:将微管蛋白抑制剂康普瑞汀(Combretastatin A4, CA4)的顺式二苯乙烯结构改造为偶氮苯类化合物,以其体内分布的特异性活化性能来增强其靶向性。方法:以3,4,5-三甲氧基苯胺为起始原料,经过重氮化反应后,与邻炔丙氧基苯酚进行偶合,得...目的:将微管蛋白抑制剂康普瑞汀(Combretastatin A4, CA4)的顺式二苯乙烯结构改造为偶氮苯类化合物,以其体内分布的特异性活化性能来增强其靶向性。方法:以3,4,5-三甲氧基苯胺为起始原料,经过重氮化反应后,与邻炔丙氧基苯酚进行偶合,得到关键中间体AzO-OH;关键中间体进一步与碘甲烷、溴丙烷或溴代正丁烷在K2CO3存在下进行酚羟基的取代反应,得到产物AzO-Me,AzO-Pr,AzO-Bu。结果:设计并合成得到CA4的偶氮化衍生物,其结构经NMR、MS确证;分子对接表明,该类化合物与微管蛋白具有较强的结合性,其结合模式与顺式CA4相近,因而可能具有类似或更强的微管蛋白抑制作用;光学性能研究发现,该类偶氮化合物在不同波长光照下会发生顺-反或反-顺的构型变化;初步的药理实验的结果显示,细胞增殖抑制活性在光照后大大提高。结论:将CA4改造为偶氮苯类化合物后,通常情况下以无生物活性但性质更稳定的反式结构存在,而在体内靶部位给予特定波段的光,就可以转化为具有活性的顺式结构发挥作用,从而可以实现“全身给药,局部激活”的靶向性能,加强了CA4的靶向性,初步的药理实验证实了上述设想。Objective: To transform the cis-stilbene structure of the tubulin inhibitor Combretastatin A4 (CA4) into an azobenzene compound, so as to enhance its targeting ability in vivo. Method: The starting material 3,4,5-trimethoxyaniline was diazotized, then coupling with o-propargyloxyphenol to obtain the key intermediate AzO-OH;the key intermediate was further substituted with the reaction of the phenolic hydroxyl group to obtain the product AzO-Me, AzO-Pr, AzO-Bu, by combining with methyl iodide, bromopropane or bromo-n-butane in the presence of K2CO3. Results: The azo derivatives of CA4 were synthesized. Their structures were confirmed by NMR and MS. Molecular docking showed that these compounds had strong binding activities to tubulin, and the binding modes were similar to that of cis-CA4. So they may have a similar or stronger inhibitory effect on tubulin. Optical performance studies have found that this type of azo compound undergoes a cis to trans or trans to cis configuration changes under different wavelengths of light. The results of preliminary pharmacological experiments showed that the inhibitory activity of cell proliferation was greatly improved after illumination. Conclusions: After transforming CA4 into azobenzene compound, it usually exists as a stable trans-structure with no or little biological activity. However, given a specific wavelength of light at the target site in the body, it can be converted into an active cis-form. The structure plays an important role, so that the targeting performance of “systemic administration, local activation” can be realized, and the targeting ability of CA4 can be enhanced. Preliminary pharmacological experiments confirmed the hypothesis.展开更多
Heterostructures from two-dimensional transition-metal dichalcogenides MX2 have emerged as a hot topic in recent years due to their various fascinating properties. Here, we investigated the temperature dependent Raman...Heterostructures from two-dimensional transition-metal dichalcogenides MX2 have emerged as a hot topic in recent years due to their various fascinating properties. Here, we investigated the temperature dependent Raman and photoluminescence （PL） spectra in vertical stacked WS2/MoS2 monolayer heterostructures. Our result shows that both E^g and Alg modes of WS2 and MoS2 vary linearly with tem- perature increasing from 300 to 642 K. The PL measurement also reveals strong temperature dependencies of the PL intensity and peak position. The activation energy of the thermal quenching of the PL emission has been found to be equal to 69.6 meV. The temperature dependence of the peak energy well follows the band- gap shrinkage of bulk semiconductor.展开更多
文摘目的:将微管蛋白抑制剂康普瑞汀(Combretastatin A4, CA4)的顺式二苯乙烯结构改造为偶氮苯类化合物,以其体内分布的特异性活化性能来增强其靶向性。方法:以3,4,5-三甲氧基苯胺为起始原料,经过重氮化反应后,与邻炔丙氧基苯酚进行偶合,得到关键中间体AzO-OH;关键中间体进一步与碘甲烷、溴丙烷或溴代正丁烷在K2CO3存在下进行酚羟基的取代反应,得到产物AzO-Me,AzO-Pr,AzO-Bu。结果:设计并合成得到CA4的偶氮化衍生物,其结构经NMR、MS确证;分子对接表明,该类化合物与微管蛋白具有较强的结合性,其结合模式与顺式CA4相近,因而可能具有类似或更强的微管蛋白抑制作用;光学性能研究发现,该类偶氮化合物在不同波长光照下会发生顺-反或反-顺的构型变化;初步的药理实验的结果显示,细胞增殖抑制活性在光照后大大提高。结论:将CA4改造为偶氮苯类化合物后,通常情况下以无生物活性但性质更稳定的反式结构存在,而在体内靶部位给予特定波段的光,就可以转化为具有活性的顺式结构发挥作用,从而可以实现“全身给药,局部激活”的靶向性能,加强了CA4的靶向性,初步的药理实验证实了上述设想。Objective: To transform the cis-stilbene structure of the tubulin inhibitor Combretastatin A4 (CA4) into an azobenzene compound, so as to enhance its targeting ability in vivo. Method: The starting material 3,4,5-trimethoxyaniline was diazotized, then coupling with o-propargyloxyphenol to obtain the key intermediate AzO-OH;the key intermediate was further substituted with the reaction of the phenolic hydroxyl group to obtain the product AzO-Me, AzO-Pr, AzO-Bu, by combining with methyl iodide, bromopropane or bromo-n-butane in the presence of K2CO3. Results: The azo derivatives of CA4 were synthesized. Their structures were confirmed by NMR and MS. Molecular docking showed that these compounds had strong binding activities to tubulin, and the binding modes were similar to that of cis-CA4. So they may have a similar or stronger inhibitory effect on tubulin. Optical performance studies have found that this type of azo compound undergoes a cis to trans or trans to cis configuration changes under different wavelengths of light. The results of preliminary pharmacological experiments showed that the inhibitory activity of cell proliferation was greatly improved after illumination. Conclusions: After transforming CA4 into azobenzene compound, it usually exists as a stable trans-structure with no or little biological activity. However, given a specific wavelength of light at the target site in the body, it can be converted into an active cis-form. The structure plays an important role, so that the targeting performance of “systemic administration, local activation” can be realized, and the targeting ability of CA4 can be enhanced. Preliminary pharmacological experiments confirmed the hypothesis.
基金supported by the National Basic Research Program of China (2015CB932403)the National Natural Science Foundation of China (11674012, 61422501, 11374023, 11304054 and 61521004)+2 种基金Beijing Natural Science Foundation (L140007)Foundation for the Author of National Excellent Doctoral Dissertation of China (201420)National Program for Support of Top-notch Young Professionals
文摘Heterostructures from two-dimensional transition-metal dichalcogenides MX2 have emerged as a hot topic in recent years due to their various fascinating properties. Here, we investigated the temperature dependent Raman and photoluminescence （PL） spectra in vertical stacked WS2/MoS2 monolayer heterostructures. Our result shows that both E^g and Alg modes of WS2 and MoS2 vary linearly with tem- perature increasing from 300 to 642 K. The PL measurement also reveals strong temperature dependencies of the PL intensity and peak position. The activation energy of the thermal quenching of the PL emission has been found to be equal to 69.6 meV. The temperature dependence of the peak energy well follows the band- gap shrinkage of bulk semiconductor.
